Therapeutic compounds for treating dyslipidemic conditions

ABSTRACT

The present invention relates to novel LXR ligands of Formula I and the pharmaceutically acceptable salts, esters and tautomers thereof, which are useful in the treatment of dyslipidemic conditions, particularly depressed levels of HDL cholesterol.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. § 371 filing from InternationalApplication No. PCT/US03/22807, filed Jul. 21, 2003, which claims thebenefit under 35 U.S.C. 119(e) of U.S. Provisional Application No.60/398,716, filed Jul. 25, 2002.

BACKGROUND OF THE INVENTION

Recent publications in Nature Genetics, August, 1999 (Young et al., page316; Bodzioch et al., page 347; Brooks-Wilson et al., page 335, and Rustet al., page 352) showed that humans with mutations in the gene ABCA1(also previously known in the art as ABC1) have low levels of highdensity lipoprotein (HDL). Low HDL levels are a risk factor foratherosclerosis, myocardial infarction and related conditions such asischemic stroke. Therefore, increasing the expression of the ABCA1 genewould be expected to increase HDL levels and decrease the occurrence ofatherosclerosis, myocardial infarction and related conditions such asischemic stroke. It has been reported that expression of the ABCA1 geneis increased by cholesterol loading of cells (Langmann et al., Biochem.Biophys. Res. Comm., 257, 29–33 (1999)). LXRα is a nuclear receptor thatis required for the induction of cholesterol 7α-hydroxylase in mouseliver following cholesterol feeding (Peet et al., Cell, 93, 693–704(1998)). LXRα and LXRβ are activated by 22-(R)-hydroxycholesterol andother oxysterols (Janowski et al. Proc. Natl. Acad. Sci USA, 96, 266–271(1999), Thomas A. Spencer et al. J. Med. Chem., 44, 886–897, (2001)).Some non-steroidal small molecule agonists of LYRα and LXRβ have beenreported to affect circulating HDL levels, cholesterol absorption,reverse cholesterol transport and ABCA1 expression in vivo (J. R.Schultz, et al. Genes & Devel. 14, 2831–2838, (2000), J. J. Repa et al.Science, 289, 1524–1529, (2000)). It has been found that LXRα and/orLXRβ cause the induction or regulation of ABCA1 expression, and thatsmall molecule ligands of LXR are useful as drugs to increase theexpression of ABCA1, increase levels of HDL and thereby decrease therisk of atherosclerosis, myocardial infarction and related conditionssuch as peripheral vascular disease and ischemic stroke.

The various dyslipidemic conditions, which are risk factors foratherosclerosis, are currently treated with several different classes ofdrugs, such as statins which are HMG-CoA reductase inhibitors, bile acidsequestrants (e.g., cholestyramine and colestipol), nicotinic acid(niacin), and fibrates. However, except for niacin, most of thesetreatments do not raise HDL as their primary effect. With favorableoutcomes in many human studies, the statin class of drugs is used tomodulate LDL and, to a lesser extent, HDL and triglycerides. Conditionsprincipally characterized by elevated plasma triglycerides and low HDLare frequently treated with drugs belonging to the fibrate class. Thefibrates are PPAR alpha agonists that lower triglycerides and raise HDLin many instances. There are no currently marketed drugs whose principalactions are mediated by LXR.

We have now discovered a new class of small molecules which are LXRligands, i.e., LXRα and/or LXRβ ligands, and are therefore expected tobe useful for modulation of HDL levels, ABCA1 gene expression andreverse cholesterol transport. The instant compounds have been shown toraise plasma levels of HDL in animal models and to increase cholesterolefflux from cells in vitro. These biological activities are critical forreverse cholesterol transport.

The novel compounds of this invention are intended as a treatment fordyslipidemias, especially low plasma HDL cholesterol levels, as well asfor treatment and/or prevention of lipid accumulation in atheroscleroticplaques, which is an underlying cause or aggravating factor inatherosclerosis.

SUMMARY OF THE INVENTION

Compounds of Formula I are novel LXR ligands and are useful in thetreatment of dyslipidemic conditions including below-desirable levels ofHDL cholesterol.

One object of the instant invention is to provide a method for treatingdepressed plasma HDL cholesterol levels comprising administering atherapeutically effective amount of a compound of Formula I to a patientin need of such treatment.

Another object is to provide a method for preventing or treatingdyslipidemic conditions comprising administering a prophylactically ortherapeutically effective amount, as appropriate, of a compound ofFormula I to a patient in need of such treatment.

As a further object, methods are provided for preventing or reducing therisk of developing atherosclerosis, as well as for halting or slowingthe progression of atherosclerotic disease once it has become clinicallyevident, comprising the administration of a prophylactically ortherapeutically effective amount, as appropriate, of a compound ofFormula I to a patient who is at risk of developing atherosclerosis orwho already has atherosclerotic disease. The method of this inventionalso serves to remove cholesterol from tissue deposits such as xanthomasand atherosclerotic lesions by hastening the efflux of cholesterol fromcells in those lesions.

Another object of the present invention is the use of the compounds ofthe present invention for the manufacture of a medicament useful intreating, preventing or reducing the risk of developing theseconditions.

Other objects of this invention are to provide processes for making thecompounds of Formula I and to provide novel pharmaceutical compositionscomprising these compounds. Additional objects will be evident from thefollowing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The novel LXR ligands of the instant invention are compounds of FormulaI

and the pharmaceutically acceptable salts, esters and tautomers thereof,wherein

-   R¹ is selected from the group consisting of:    -   (a) —CF₃,    -   (b) —CH₂C(CH₃)₃,    -   (c) phenyl, unsubstituted, mono- or poly-substituted with halo,    -   (d) —C₁₋₆alkyl, and    -   (e) —C₁₋₂alkyl-phenyl;-   R² is selected from the group consisting of:    -   (a) —C₁₋₆alkyl,    -   (b) —COOR³,    -   (c) —CR³R⁴—O—R⁵,    -   (d) —CR³R⁴—S—R⁵, and    -   (e) —COR³;-   R³, R⁴ and R⁵ are independently selected at each occurrence from the    group consisting of —H, phenyl, and C₁₋₆alkyl;-   Y is joined together with the nitrogen and the carbonyl carbon shown    in Formula I to which Y is respectively attached, to form a    heterocyclic ring selected from:    -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

-   -   (d) a bicyclic heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷;

-   R⁶ is independently selected at each occurrence from the group    consisting of:    -   (a) —H,    -   (b) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —NR³R⁴, —OR³, —COOR³, and —CN,    -   (c) —C₁₋₆alkyl-phenyl, unsubstituted, mono- or poly-substituted        with a substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (d) —C₃₋₆cycloalkyl, unsubstituted, mono- or poly-substituted        with a substituent selected from the group consisting of halo,        —OH, —OR³, —COOR³, and —CN,    -   (e) —C₃₋₆cycloheteroalkyl, unsubstituted, mono- or        poly-substituted with a substituent selected from the group        consisting of halo, —OH, —(CH₂)_(n)OR³, —OR³, —COOR³, and —CN,        wherein n is an integer selected from 2, 3, 4, 5 and 6,    -   (f) —C₂₋₆alkenyl,    -   (g) —C(O)C₁₋₆alkyl,    -   (h) —COOR³,    -   (i) —C(O)—(CH₂)_(p)—COOR³, wherein p is an integer selected from        2, 3 and 4,    -   (j) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (k) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (l) pyrimidinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (m) pyrazinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³, and    -   (n) thiazolyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³;-   R⁷ is independently selected at each occurrence from the group    consisting of:    -   (a) ═O,    -   (b) —C₁₋₆alkyl-phenyl, unsubstituted, mono- or poly-substituted        with a substituent selected from the group consisting of halo,        —CN, —COOR³, —COR³, and —OH,    -   (c) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —COOR³, tetrazole and —CN,    -   (d) —C₃₋₆cycloalkyl,    -   (e) —C₃₋₆spiroalkyl,    -   (f) —COOR³,    -   (g) halo,    -   (h) —NR³R⁴,    -   (i) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —COOR³        and —C₁₋₄alkyl,    -   (j) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (k) pyrimidinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₃alkyl, and —COOR³, and    -   (l) pyrazinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₃alkyl, and —COOR³; and-   Z is selected from the group consisting of:    -   (a) —C₁₋₆alkyl-,    -   (b) —C₁₋₆alkyl-O—,    -   (c) —C₃₋₆cycloalkyl-, and    -   (d) —C₃₋₆cycloalkyl-O—.

In one embodiment of the present invention are those compounds ofFormula I wherein R¹ is selected from the group consisting of:

-   -   (a) —CF₃,    -   (b) —CH₂C(CH₃)₃, and    -   (c) phenyl, unsubstituted, mono- or poly-substituted with halo.

In a class of this embodiment are those compounds of Formula I whereinR¹ is selected from the group consisting of:

-   -   (a) —CF₃, and    -   (b) phenyl, unsubstituted, mono- or poly-substituted with halo.

In a subclass of this embodiment are those compounds of Formula Iwherein R¹ is —CF₃.

In a second embodiment of the present invention are those compounds ofFormula I wherein R² is selected from the group consisting of:

-   -   (a) —C₁₋₆alkyl, and    -   (b) —COR³.

In a class of this embodiment are those compounds of Formula I whereinR² is —C₁₋₆alkyl.

In sub-class of this class are those compounds of Formula I wherein R²is n-propyl.

In third embodiment of this invention are those compounds of Formula Iwherein Y is joined together with the nitrogen and the carbonyl carbonshown in Formula I to which Y is respectively attached, to form aheterocyclic ring selected from:

-   -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.

In a class of the third embodiment of this invention are those compoundsof Formula I wherein Y is joined together with the nitrogen and thecarbonyl carbon shown in Formula I to which Y is respectively attached,to form a heterocyclic ring selected from:

-   -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.

In a subclass of this class are those compounds of Formula I wherein Yis joined together with the nitrogen and the carbonyl carbon shown inFormula I to which Y is respectively attached, to form a heterocyclicring selected from:

-   -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.

In a fourth embodiment of this invention are those compounds of FormulaI wherein R⁶ is independently selected at each occurrence from the groupconsisting of:

-   -   (a) —H,    -   (b) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —NR³R⁴, —OR³, —COOR³, and —CN,    -   (c) —C₁₋₆alkyl-phenyl, unsubstituted, mono- or poly-substituted        with a substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (d) —C(O)—(CH₂)_(p)—COOR³, wherein p is an integer selected from        2, 3 and 4,    -   (e) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (f) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³, and    -   (g) pyrimidinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³.

In a fifth embodiment of this invention are those compounds of Formula Iwherein R⁷ is independently selected at each occurrence from the groupconsisting of:

-   -   (a) ═O,    -   (b) —CH₂-phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —CN,        —COOR³, —COR³ and —OH,    -   (c) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —COOR³, tetrazole and —CN,    -   (d) halo,    -   (e) —NH₂,    -   (f) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —COOR³        and —C₁₋₄alkyl,    -   (g) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (h) pyrimidinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³, and    -   (i) pyrazinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³.

In a class of the fifth embodiment are those compounds of Formula Iwherein R⁷ is independently selected at each occurrence from the groupconsisting of:

-   -   (a) ═O,    -   (b) —CH₂-phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —CN,        —COOR³, —COR³, and —OH,    -   (c) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —COOR³, tetrazole and —CN,    -   (d) halo,    -   (e) —NH₂,    -   (f) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —COOR³        and —C₁₋₄alkyl, and    -   (g) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³.

In a sixth embodiment of the present invention are compounds of FormulaI wherein Z is —C₂₋₄alkyl-O—.

In one class of the sixth embodiment are those compounds of Formula Iwherein R¹ is selected from the group consisting of —CF₃, —CH₂C(CH₃)₃,and phenyl unsubstituted, mono- or poly-substituted with halo; R² isselected from the group consisting of —C₁₋₆alkyl and —COR³; and R³, R⁴and R⁵ are independently selected at each occurrence from the groupconsisting of —H, phenyl, —CH₂-phenyl, and —C₁₋₆alkyl. Within thisclass, R² is particularly —C₁₋₆alkyl, and more particularly R² isn-propyl.

In sub-class (i) of this class of the sixth embodiment are compoundswherein R² is n-propyl, and Y is joined together with the nitrogen andthe carbonyl carbon shown in Formula I to which Y is respectivelyattached, to form a heterocyclic ring selected from:

-   -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.

Particularly in sub-class (i) of this class are compounds of Formula Iwherein R⁶ is independently selected at each occurrence from the groupconsisting of:

-   -   (a) —H,    -   (b) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —NR³R⁴, —OR³, —COOR³, and —CN,    -   (c) —C₁₋₆alkyl-phenyl, unsubstituted, mono- or poly-substituted        with a substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (d) —C(O)—(CH₂)_(p)—COOR³, wherein p is an integer selected from        2, 3 and 4,    -   (e) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³,    -   (f) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³, and    -   (g) pyrimidinyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³.

More particularly, in sub-class (i) of this class are compounds whereinR⁷ is independently selected at each occurrence from the groupconsisting of:

-   -   (a) ═O,    -   (b) —CH₂-phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —CN,        —COOR³, —COR³ and —OH,    -   (c) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —OH,        —COOR³, tetrazole and —CN,    -   (d) halo,    -   (e) —NH₂,    -   (f) phenyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo, —COOR³,        and —C₁₋₄alkyl, and    -   (g) pyridyl, unsubstituted, mono- or poly-substituted with a        substituent selected from the group consisting of halo,        —C₁₋₃alkyl, and —COOR³.

In sub-class (ii) of the this class of the sixth embodiment arecompounds wherein R¹ is selected from the group consisting of —CF₃, andphenyl, unsubstituted, mono- or poly-substituted with halo, and R² isn-propyl.

Particularly, in sub-class (ii) of this class are compounds wherein Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I to which Y is respectively attached, to form a heterocyclicring selected from:

-   -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.

Specific compounds within sub-class (ii) of this class are:

-   (1)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one,-   (2)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (3)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione,-   (4)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (5)    1-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (6)    5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (7)    1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (8)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dione,-   (9)    rac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (10)    rac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione,-   (11)    rac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (12)    rac-5-methyl-5-(3-carboxyphenyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (13)    rac-5-methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (14)    rac-3-[2,5-dioxo-4-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-4-yl]propanoic    acid,-   (15)    2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoic    acid,-   (16)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one,-   (17)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione,-   (18)    1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione,-   (19)    3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione,-   (20)    6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (21)    1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (22)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione,-   (23)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione,    and-   (24)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one,    and pharmaceutically acceptable salts, esters and tautomers thereof.

In sub-class (iii) of this class of the sixth embodiment are compoundswherein R¹ is —CF₃ and R² is n-propyl.

Particularly, in sub-class (iii) of this class are compounds wherein Yis joined together with the nitrogen and the carbonyl carbon shown inFormula I to which Y is respectively attached, to form a heterocyclicring selected from:

-   -   (a) a 5-membered heterocyclic ring selected from the group        consisting of:

-   -   (b) a 6-membered heterocyclic ring selected from the group        consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent selected at each occurrence from R⁷.

Specific compounds within sub-class (iii) of this class are:

-   (1)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one,-   (2)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (3)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione,-   (4)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (5)    1-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (6)    5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (7)    1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (8)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dione,-   (9)    rac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (10)    rac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione,-   (11)    rac-5-methyl-5-(3-carboxyphenyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (12)    rac-5-methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (13)    rac-3-[2,5-dioxo-4-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-4-yl]propanoic    acid,-   (14)    2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoic    acid,-   (15)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one,-   (16)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione,-   (17)    1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione,-   (18)    6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)dione,-   (19)    1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (20)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione,-   (21)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione,    and-   (22)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one,    and pharmaceutically acceptable salts, esters and tautomers thereof.

In an seventh embodiment of the present invention are those compounds ofFormula I wherein Z is —C₃₋₆cycloalkyl-O—.

Specific compounds within this embodiment are:

-   (1)    1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione,    and-   (2)    1-[trans-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione,    and pharmaceutically acceptable salts, esters and tautomers thereof.

In a eighth embodiment of the present invention are those compounds ofFormula I wherein Z is —C₄₋₆alkyl-.

Specific compounds within this embodiment are:

-   1-{4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl}dihydropyrimidine-2,4(1H,3H)-dione,    and pharmaceutically acceptable salts, esters and tautomers thereof.

Another aspect of the present invention, which applies to all of theembodiments of this invention, provides that when R₁ is —CF₃, R₂ isn-propyl, and Z is n-propyloxy, the 6-membered heterocyclic ring is notunsubstituted 5,6-dihydrouracil, as shown immediately below:

Particular novel compounds of structural Formula I which may be employedin the methods, uses and compositions of the present invention, include:

-   (1)    1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (2)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (3)    2-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1H-isoindole-1,3    (2H)-dione,-   (4)    3,3-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (5)    3-methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (6)    3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione,-   (7)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione,-   (8)    5,5-dimethyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione,-   (9)    [2,4-dioxo-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3-thiazolidin-5-yl]acetic    acid,-   (10)    3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (11)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (12)    1-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (13)    5(R)-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (14)    5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (15)    1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (16)    5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (17)    5-methyl-5-phenyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (18)    5-methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (19)    5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione,-   (20)    5-methyl-5-(3-carboxyphenyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (21)    5-methyl-5-(4-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (22)    5-methyl-5-(3-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (23)    5-methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (24)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrimidin-2-ylimidazolidine-2,4-dione,-   (25)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dione,-   (26)    3-[2,5-dioxo-4-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-4-yl]propanoic    acid,-   (27)    4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]butanoic    acid,-   (28)    4-[5,5-methyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoic    acid,-   (29)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one,-   (30) methyl    2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoate,-   (31)    2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoic    acid,-   (32)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (33)    5,5-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (34)    1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione,-   (35)    1-[trans-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione,-   (36)    1-{4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl}dihydropyrimidine-2,4(1H,3H)-dione,-   (37)    5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-7-dione,-   (38)    6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (39)    5-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (40)    1,5-Dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (41)    1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (42)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione,-   (43)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione,-   (44)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dione,-   (45)    1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one,-   (46)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one,-   (47)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione,-   (48)    1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione,-   (49)    4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dione,-   (50)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2,5-dione,-   (51)    4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-one,-   (52)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3,5-triazinane-2,4-dione,-   (53)    3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (54)    6-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,    and-   (55) (1)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one,    and pharmaceutically acceptable salts, esters and tautomers thereof.

One subclass of compounds of the present invention includes compoundswherein R¹ is —CF₃ or phenyl, and R² is n-propyl. Particular compoundsof this subclass include:

-   (1)    11-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one,-   (2)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione,-   (3)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione,-   (4)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (5)    1-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (6)    5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (7)    1-Phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (8)    1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (9)    5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (10)    5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione,-   (11)    5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (12)    5-(3-carboxyphenyl)-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (13)    5-(2-Pyridyl)-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (14)    5-Phenyl-5-(3-propionyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione,-   (15)    2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoic    acid,-   (16)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one,-   (17)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione,-   (18)    1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione,-   (19)    1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione,-   (20)    3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione,-   (21)    6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (22)    1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione,-   (23)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione,-   (24)    3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione,    and-   (25)    1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one,    and pharmaceutically acceptable salts, esters and tautomers thereof.

As used herein “alkyl” is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. Examples of alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl(Bu), n-pentyl, n-hexyl, and the isomers thereof such as isopropyl(i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), isopentyl,isohexyl and the like.

The term “C₂₋₆alkenyl” as used herein, refers to a straight or branched2–6 carbon chain with at least one carbon-carbon double bond. Examplesof alkenyl include, but are not limited to, vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“C₃₋₆cycloalkyl” means a monocyclic saturated carbocyclic ring, havingfrom 3 to 6 carbon atoms, wherein one carbocyclic ring carbon is thepoint of attachment. Examples of cycloalkyl include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“C₃₋₆spiroalkyl” means a monocyclic saturated cycloalkyl ring, havingfrom 3 to 6 carbon atoms, wherein the spiro union is formed by a singlecarbon atom which is the only common carbon atom of two cycloalkylrings. An example of a C₃ spiroalkyl substituent is equivalent to

“C₃₋₆cycloheteroalkyl” means a monocyclic saturated ring containing atleast one heteroatom selected from N, S and O, each of said ring havingfrom 3 to 6 atoms in which the point of attachment may be carbon ornitrogen. Examples of “cycloheteroalkyl” include, but are not limitedto, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl,tetrahydrofuranyl, morpholinyl, and the like.

The terms “halo” or “halogen” are meant to include fluoro, chloro, bromoand iodo, unless otherwise noted. Fluoro is preferred.

Herein, the term “pharmaceutically acceptable salts” shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenzimidazole, diethylamine,piperazine, morpholine, 2,4,4-trimethyl-2-pentamine andtris(hydroxymethyl)aminomethane. Pharmaceutically acceptable esters atthe carboxylic acid group can be made by treating a dihydroxy open acidstatin with an alcohol. Examples of pharmaceutically acceptable estersinclude, but are not limited to, —C₁₋₄alkyl and —C₁₋₄alkyl substitutedwith phenyl-, dimethylamino-, and acetylamino. “C₁₋₄alkyl” hereinincludes straight or branched aliphatic chains containing from 1 to 4carbon atoms, for example methyl, ethyl, n-propyl, n-butyl, iso-propyl,sec-butyl and tert-butyl.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅alkylcarbonylamino C₁₋₆alkyl substituent isequivalent to

When referring to moieties which may optionally be substituted herein,e.g., alkyl groups, cycloalkyl groups, phenyl groups, heterocycloalkylgroups, and the like, the phrases used herein “unsubstituted, mono- ordi-substituted with a substituent independently selected at eachoccurrence” and “unsubstituted, mono- or poly-substituted with asubstituent selected from” are intended to mean that the total number ofsubstituents on the moiety overall may be zero, one or more than one,and that each carbon and nitrogen atom available for substitution in thegiven moiety may independently be unsubstituted or mono- orpoly-substituted, with one or more substituents that are the same ordifferent at each occurrence and which result in the creation of astable structure. The term “poly-substituted” is intended to mean two ormore substituents, e.g. di-, tri-, tetra-, penta-substitution and higheras appropriate.

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability. When any variable (e.g., R¹, R²,etc.) occurs more than one time in any constituent or in formula I, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,enantiomeric mixtures, diastereomeric mixtures and individualdiastereomers. The present invention is meant to comprehend all suchisomeric forms of the compounds of Formula I. All such isomeric forms ofthe compounds of Formula I are included within the scope of thisinvention.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers of thecompounds of Formula I, as well as mixtures thereof, are included in thescope of this invention. By way of illustration, tautomers included inthis definition include, but are not limited to:

The term “rac” means racemic mixture, which is defined as a mixturecomprised of equal amounts of enantiomers. If desired, racemic mixturesof compounds of Formula I may be separated by the coupling of a racemicmixture of the compounds of Formula I to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediasteromeric derivatives may then be converted to the pure enantiomersby cleavage and removal of the added chiral residue. The racemic mixtureof the compounds of Formula I can also be separated directly bychromatographic methods utilizing chiral stationary phases, whichmethods are well known in the art.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration. Such methods are wellknown in the art.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

Some abbreviations used herein are as follows: Ac is acetyl [CH₃C(O)—];PG is protecting group; LG is leaving group; Ac₂O is acetic anhydride;9-BBN is 9-borabicyclo[3.3.1]nonane; Pd(dba)₂ istris(dibenzylideneacetone)dipalladium, PdCl2dppf isdichlorobis-(triphenylphosphene) palladium, Ph is phenyl; PhMe istoluene; PPh₃ is triphenylphosphine; Bn is benzyl; Me is methyl, Et isethyl, EtOH is ethanol, EtOAc is ethyl acetate, Et₃N is triethylamine,tBu is tert-butyl, PMB is para-methoxybenzyl; DMF isN,N-dimethylformamide; DMSO is dimethyl sulfoxide; DIAD isdiisopropylazodicarboxylate; Tf₂O is triflic anhydride, Tf is triflate,TBAF is tetrabutyl ammonium fluoride; THF is tetrahydrofuran; TMS istrimethylsilyl; TBS is tert-butyldimethylsilyl; HOBt is1-hydroxybenzotriazole; EDAC (or EDC) is1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide HCl; HCl ishydrochloric acid; NaHMDS is sodium hexamethyldisiliazide; DIBAL isdiisobutylaluminum hydride; TPAP is tetrapropylammonium perruthenate;NMO is N-methylmorpholine N oxide; MsCl methanesulfonyl chloride; HPLCis high performance liquid chromatography; NaOAc is sodium acetate;NaOtBu is sodium tert-butoxide, TLC is thin layer chromatography; RT isroom temperature; N is normal; mmol is millimole; M is molar; TFA istrifluoroacetic acid.

General Schemes

The compounds of this invention can be prepared employing the followinggeneral procedures. Benzisoxazole intermediates may be prepared fromcommercially available or readily accessible resorcinols as shown inScheme 1 or alternate synthetic pathways as reported in the literature.See for example: Shutske, G. M. et al. J. Med. Chem., 25 (1), 36,(1982); Poissonnet, G. Synth. Commun., 27 (22), 3839–3846, (1997);Crabbe, P. Villarino, A. Muchowski, J. M. J. Chem. Soc., Perkin Trans 1,1973, 2220.

For maximum flexibility these phenolic benzisoxazoles may be convertedto intermediate alkylating agents for condensation with a variety ofheterocyclic substrates, as shown in Scheme 2 below. Alkylation with amore elaborate alkylating agent can lead directly to the desiredcompounds.

As an alternative approach, or for use where the bromide or halideintermediates might be difficult to access, many variations of theMitsunobu coupling can also be used to construct these compounds asindicated in Scheme 3 below.

In many of the current examples, the heterocyclic partner will becommercially available or accessible by well known methods. Severalexamples derive from substituted hydantoins and dihydropyrimidinediones.In addition to the various published routes to these intermediates, thegeneral procedures of Schemes 4 and 5 have been found to give access tothe desired intermediate heteroaryls. In Scheme 4, R′ and R″ are alkylor aryl substituents as desired, and the ester residue R′″ can also bealkyl or aryl as desired.

The desired heterocyclic fragments are prepared as shown in Schemes 4and 5 below. Depending on the exact example chosen, the heterocyclicintermediate is then converted to the desired final product as shown inschemes 2 and 3.

Many of the N-aryl and N-heteroaryl analogs claimed here are accessiblethrough palladium(0) mediated couplings of nitrogen heterocycles with anaryl or heteroaryl halide partner as typified by Scheme 5. R′ in Scheme5 can be a protecting group, a partially or a completely elaboratedfragment of the desired target.

The instant invention provides methods for treating lipid disorders,particularly for treating below-desired plasma HDL cholesterol levels,as well as for treating and/or reducing the risk for diseases andconditions affected by LXR activity, comprising administering atherapeutically effective amount of a compound of Formula I to a personin need of such treatment. Any patient having a depressed plasma HDLcholesterol level, or desiring to increase their HDL cholesterol levelmay use this treatment. Particularly suitable patients in need of suchtreatment are those whose plasma HDL cholesterol level is depressed,i.e., below the clinically desirable level. Currently, the clinicallydesirable HDL cholesterol level is considered to be about 40 mg/dl orhigher in men and about 50 mg/dl or higher in women.

The method of this invention also serves to prevent lipid accumulationin, or remove lipids from, tissue deposits such as atheroscleroticplaques or xanthomas in a patient with atherosclerotic disease manifestby clinical signs such as angina, claudication, bruits, one that hassuffered a myocardial infarction or transient ischemic attack, or onediagnosed by angiography, sonography or MRI.

Further provided are methods for preventing or reducing the risk ofdeveloping atherosclerosis, as well as for halting or slowing theprogression of atherosclerotic disease once it has become clinicallyevident, comprising the administration of a prophylactically ortherapeutically effective amount, as appropriate, of a compound ofFormula I to a mammal, including a human, who is at risk of developingatherosclerosis or who already has atherosclerotic disease.

Atherosclerosis encompasses vascular diseases and conditions that arerecognized and understood by physicians practicing in the relevantfields of medicine. Atherosclerotic cardiovascular disease includingrestenosis following revascularization procedures, coronary heartdisease (also known as coronary artery disease or ischemic heartdisease), cerebrovascular disease including multi-infarct dementia, andperipheral vessel disease including erectile dysfunction are allclinical manifestations of atherosclerosis and are therefore encompassedby the terms “atherosclerosis” and “atherosclerotic disease.”

A compound of Formula I may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, and/orintermittent claudication. Coronary heart disease (CHD) events areintended to include CHD death, myocardial infarction (i.e., a heartattack), and coronary revascularization procedures. Cerebrovascularevents are intended to include ischemic or hemorrhagic stroke (alsoknown as cerebrovascular accidents) and transient ischemic attacks.Intermittent claudication is a clinical manifestation of peripheralvessel disease. The term “atherosclerotic disease event” as used hereinis intended to encompass coronary heart disease events, cerebrovascularevents, and intermittent claudication. It is intended that persons whohave previously experienced one or more non-fatal atheroscleroticdisease events are those for whom the potential for recurrence of suchan event exists.

Accordingly, the instant invention also provides a method for preventingor reducing the risk of a first or subsequent occurrence of anatherosclerotic disease event comprising the administration of aprophylactically effective amount of a compound of Formula I to apatient at risk for such an event. The patient may or may not haveatherosclerotic disease at the time of administration, or may be at riskfor developing it.

Persons to be treated with the instant therapy include those withdyslipidemic conditions including depressed or below-desirable plasmalevels of HDL cholesterol, as well as those at risk of developingatherosclerotic disease and of having an atherosclerotic disease event.Standard atherosclerotic disease risk factors are known to the averagephysician practicing in the relevant fields of medicine. Such known riskfactors include but are not limited to hypertension, smoking, diabetes,low levels of high density lipoprotein cholesterol, and a family historyof atherosclerotic cardiovascular disease. Published guidelines fordetermining those who are at risk of developing atherosclerotic diseasecan be found in: Executive Summary of the Third Report of the NationalCholesterol Education Program (NCEP) Expert Panel on Detection,Evaluation, and Treatment of High Blood Cholesterol in Adults (AdultTreatment Panel III), JAMA, 2001; 285 pp. 2486–2497. People who areidentified as having one or more of the above-noted risk factors areintended to be included in the group of people considered at risk fordeveloping atherosclerotic disease. People identified as having one ormore of the above-noted risk factors, as well as people who already haveatherosclerosis, are intended to be included within the group of peopleconsidered to be at risk for having an atherosclerotic disease event.

The term “patient” includes mammals, especially humans, who use theinstant active agents for the prevention or treatment of a medicalcondition. Administering of the drug to the patient includes bothself-administration and administration to the patient by another person.The patient may be in need of treatment for an existing disease ormedical condition, or may desire prophylactic treatment to prevent orreduce the risk for diseases and medical conditions affected by reversecholesterol transport.

The term “therapeutically effective amount” is intended to mean thatamount of a drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, a system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.The term “prophylactically effective amount” is intended to mean thatamount of a pharmaceutical drug that will prevent or reduce the risk ofoccurrence of the biological or medical event that is sought to beprevented in a tissue, a system, animal or human by a researcher,veterinarian, medical doctor or other clinician. Particularly, thedosage amount of a compound of Formula I that a patient receives can beselected so as to achieve the amount of lipid level modificationdesired, particularly to achieve a desired level of HDL cholesterol. Thedosage a patient receives may also be titrated over time in order toreach a target lipid profile. The dosage regimen utilizing a compound ofFormula I is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the potency of the compoundchosen to be administered; drug combinations; the route ofadministration; and the renal and hepatic function of the patient. Aconsideration of these factors is well within the purview of theordinarily skilled clinician for the purpose of determining thetherapeutically effective or prophylactically effective dosage amountneeded to prevent, counter, or arrest the progress of the condition.

An effective amount of compound for use in the method of this inventionis about 0.01 mg/kg to about 30 mg/kg of body weight per day, or about0.7 mg to about 2100 mg per patient in single or divided doses per day.More particularly, an amount of about 7 mg to about 1050 mg per patientin single or divided doses per day can be administered. However, dosageamounts will vary depending on factors as noted above, including thepotency of the particular compound. Although the active drug of thepresent invention may be administered in divided doses, for example fromone to four times daily, a single daily dose of the active drug ispreferred.

The active drug employed in the instant therapy can be administered insuch oral forms as tablets, capsules, pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. Oral formulations arepreferred.

Administration of the active drug can be via any pharmaceuticallyacceptable route and in any pharmaceutically acceptable dosage form.This includes the use of oral conventional rapid-release, timecontrolled-release and delayed-release (such as enteric coated)pharmaceutical dosage forms. Additional suitable pharmaceuticalcompositions for use with the present invention are known to those ofordinary skill in the pharmaceutical arts; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa.

In the methods of the present invention, the active drug is typicallyadministered in admixture with suitable pharmaceutical diluents,excipients or carriers (collectively referred to herein as “carrier”materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, elixirs, syrups and thelike, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with a non-toxic,pharmaceutically acceptable, inert carrier such as lactose, starch,sucrose, glucose, modified sugars, modified starches, methyl celluloseand its derivatives, dicalcium phosphate, calcium sulfate, mannitol,sorbitol and other reducing and non-reducing sugars, magnesium stearate,steric acid, sodium stearyl fumarate, glyceryl behenate, calciumstearate and the like. For oral administration in liquid form, the drugcomponents can be combined with non-toxic, pharmaceutically acceptableinert carrier such as ethanol, glycerol, water and the like. Moreover,when desired or necessary, suitable binders, lubricants, disintegratingagents and coloring and flavoring agents can also be incorporated intothe mixture. Stabilizing agents such as antioxidants, for examplebutylated hydroxyanisole (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT),propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite,hydroquinone, and 7-hydroxycoumarin, can also be added to stabilize thedosage forms. Other suitable components include gelatin, sweeteners,natural and synthetic gums such as acacia, tragacanth or alginates,carboxymethylcellulose, polyethylene glycol, waxes and the like.

The active drug can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Active drug may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Activedrug may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinyl-pyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, active drug may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels.

The instant invention also encompasses a process for preparing apharmaceutical composition comprising combining a compound of Formula Iwith a pharmaceutically acceptable carrier. Also encompassed is thepharmaceutical composition which is made by combining a compound ofFormula I with a pharmaceutically acceptable carrier.

In a broad embodiment, any suitable additional active agent or agentsmay be used in combination with the compound of Formula I in a singledosage formulation, or may be administered to the patient in a separatedosage formulation, which allows for concurrent or sequentialadministration of the active agents. One or more additional activeagents may be administered with a compound of Formula I. The additionalactive agent or agents can be lipid modifying compounds or agents havingother pharmaceutical activities, or agents that have bothlipid-modifying effects and other pharmaceutical activities. Examples ofadditional active agents which may be employed include but are notlimited to HMG-CoA reductase inhibitors, which include statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin (seeU.S. Pat. No. 4,342,767), simvastatin (see U.S. Pat. No. 4,444,784),dihydroxy open-acid simvastatin, particularly the ammonium or calciumsalts thereof, pravastatin, particularly the sodium salt thereof (seeU.S. Pat. No. 4,346,227), fluvastatin particularly the sodium saltthereof (see U.S. Pat. No. 5,354,772), atorvastatin, particularly thecalcium salt thereof (see U.S. Pat. No. 5,273,995), pitavastatin alsoreferred to as NK-104 (see PCT international publication number WO97/23200) and rosuvastatin, also known as ZD-4522, (CRESTOR®; see U.S.Pat. No. 5,260,440, and Drugs of the Future, 1999, 24(5), pp. 511–513);HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MPT)inhibitors; niacin; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors, forexample glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists including the compounds commonly referred to as glitazones forexample pioglitazone and rosiglitazone and, including those compoundsincluded within the structural class known as thiazolidine diones aswell as those PPARγ agonists outside the thiazolidine dione structuralclass; PPARα agonists such as clofibrate, fenofibrate includingmicronized fenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitaminB₆ (also known as pyridoxine) and the pharmaceutically acceptable saltsthereof such as the HCl salt; vitamin B₁₂ (also known ascyanocobalamin); folic acid or a pharmaceutically acceptable salt orester thereof such as the sodium salt and the methylglucamine salt;anti-oxidant vitamins such as vitamin C and E and beta carotene;beta-blockers; angiotensin II antagonists such as losartan; angiotensinconverting enzyme inhibitors such as enalapril and captopril; calciumchannel blockers such as nifedipine and diltiazam; endothelianantagonists; agents that enhance ABCA1 gene expression; FXR ligandsincluding both inhibitors and agonists; bisphosphonate compounds such asalendronate sodium; and cyclooxygenase-2 inhibitors such as rofecoxiband celecoxib.

Still another type of agent that can be used in combination with thecompounds of this invention are cholesterol absorption inhibitors.Cholesterol absorption inhibitors block the movement of cholesterol fromthe intestinal lumen into enterocytes of the small intestinal wall. Thisblockade is their primary mode of action in reducing serum cholesterollevels. These compounds are distinct from compounds which reduce serumcholesterol levels primarily by mechanisms of action such as acylcoenzyme A—cholesterol-acyl transferase (ACAT) inhibition, inhibition oftriglyceride synthesis, MTP inhibition, bile acid sequestration, andtranscription modulation such as agonists or antagonists of nuclearhormones. Cholesterol absorption inhibitors are described in U.S. Pat.No. 5,846,966, U.S. Pat. No. 5,631,365, U.S. Pat. No. 5,767,115, U.S.Pat. No. 6,133,001, U.S. Pat. No. 5,886,171, U.S. Pat. No. 5,856,473,U.S. Pat. No. 5,756,470, U.S. Pat. No. 5,739,321, U.S. Pat. No.5,919,672, WO 00/63703, WO/0060107, WO 00/38725, WO 00/34240, WO00/20623, WO 97/45406, WO 97/16424, WO 97/16455, and WO 95/08532, theentire contents of all of which are hereby incorporated by reference.

An exemplary cholesterol absorption inhibitor is ezetimibe, also knownas SCH-58235, which is1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,described in U.S. Pat. Nos. 5,767,115 and 5,846,966 and shown below as

Additional exemplary hydroxy-substituted azetidinone cholesterolabsorption inhibitors are specifically described in U.S. Pat. No.5,767,115, column 39, lines 54–61 and column 40, lines 1–51 (herebyincorporated by reference), represented by the formula

as defined in column 2, lines 20–63 (hereby incorporated by reference).These and other cholesterol absorption inhibitors can be identifiedaccording to the assay of hypolipidemic compounds using thehyperlipidemic hamster described in U.S. Pat. No. 5,767,115, column 19,lines 47–65 (hereby incorporated by reference), in which hamsters arefed a controlled cholesterol diet and dosed with test compounds forseven days. Plasma lipid analysis is conducted and data is reported aspercent reduction of lipid versus control.

Therapeutically effective amounts of cholesterol absorption inhibitorsinclude dosages of from about 0.01 mg/kg to about 30 mg/kg of bodyweight per day, preferably about 0.1 mg/kg to about 15 mg/kg. For anaverage body weight of 70 kg, the dosage level is therefore from about0.7 mg to about 2100 mg of drug per day, e.g. 10, 20, 40, 100 or 200 mgper day, preferably given as a single daily dose or in divided doses twoto six times a day, or in sustained release form. This dosage regimenmay be adjusted to provide the optimal therapeutic response when thecholesterol absorption inhibitor is used in combination with a compoundof the instant invention.

According to a further aspect of the present invention there is providedthe use of a compound of Formula I for the manufacture of a medicamentfor the treatment, prevention, or reduction in risk of developing a LXRreceptor mediated disease. A therapeutically or prophylacticallyeffective amount, as appropriate, of a compound of Formula I can be usedfor the preparation of a medicament useful for treating lipid disorders,particularly for treating depressed HDL cholesterol levels as well asfor treating and/or reducing the risk for diseases and conditionsaffected by agonism of LXR and affected by reverse cholesteroltransport, preventing or reducing the risk of developing atheroscleroticdisease, halting or slowing the progression of atherosclerotic diseaseonce it has become clinically manifest, and preventing or reducing therisk of a first or subsequent occurrence of an atherosclerotic diseaseevent. For example, the medicament may be comprised of about 0.7 mg toabout 2100 mg of a compound of Formula I, or more particularly about 7mg to about 1050 mg. The medicament comprised of a compound of Formula Imay also be prepared with one or more additional active agents, such asthose described supra.

As used herein, the term LXR includes all subtypes of this receptor. Thecompounds of Formula I are LXR ligands and individually may vary intheir selectivity for one or the other of LXRα and LXRβ, or they mayhave mixed binding affinity for both LXRα and LXRβ. More particularly,the tested compounds included within the scope of this invention have anIC₅₀ less than or equal to 2 μM for at least one of either the LXRα orLXRβ receptors employing the LXR radioligand competition scintillationproximity assays described below in the Example section. Preferredtested compounds of Formula I bind to the human LXRα receptor and havean IC₅₀ less than or equal to 300 nM for the LXRα receptor.

Compound A is used in the following assays and has the followingstructural formula:

Compound A and related compounds are disclosed along with methods formaking them in WO97/28137 herein incorporated by reference in itsentirety (U.S. Ser. No. 08/791,211, filed Jan. 31, 1997).

The compounds in the following examples were characterized using ¹H NMRat 400 or 500 MHz field strength, and/or by ESI mass spectroscopy (MS).

EXAMPLE 1

Radioligand Competition Binding Scintillation Proximity Assays

Preparation of Recombinant Human LXRα and LXRβ

Human LXRα and LXRβ were expressed as GST-fusion proteins in E. coli.The ligand binding domain cDNAs for human LXRα (amino acids 164–447) andhuman LXRβ (amino acids 149–455) were subcloned into the pGEX-KTexpression vector (Pharmacia). E. coli containing the respectiveplasmids were propagated, induced, and harvested by centrifugation. There-suspended pellet was broken in a French press and debris was removedby centrifugation. Recombinant human LXR receptors were purified byaffinity chromatography on glutathione sepharose and receptor was elutedwith glutathione. Glycerol was added to a final concentration of 50% tostabilize the receptor and aliquots were stored at −80° C.

Binding to LXRα:

For each assay, an aliquot of human GST-LXRα receptor was incubated in afinal volume of 100 μl SPA buffer (10 mM Tris, pH 7.2, 1 mM EDTA, 10%glycerol, 10 mM Na molybdate, 1 mM dithiothreitol, and 2 μg/mlbenzamidine) containing 1.25 mg/ml yttrium silicate protein A coated SPAbeads (Amersham Pharmacia Biotech, Inc.), 8.3 μg/ml anti-GST antibody(Amersham Pharmacia Biotech, Inc.), 0.1% non-fat dry milk and 25 nM[³H₂]Compound A (13.4 Ci/mmole), ±test compound. After incubation for˜16 h at 15° C. with shaking, the assay plates were counted in a PackardTopcount. In this assay the K_(d) for Compound A for LXRα is ≈15 nM.

Binding to LXRβ:

For each assay, an aliquot of human GST-LXRβ ligand binding domainreceptor was incubated in a final volume of 100 μl SPA buffer (10 mMTris, pH 7.2, 1 mM EDTA, 10% glycerol, 10 mM Na molybdate, 1 mMdithiothreitol, and 2 μg/ml benzamidine) containing 1.25 mg/ml yttriumsilicate protein A coated SPA beads (Amersham Pharmacia Biotech, Inc.),8.3 μg/ml anti-GST antibody (Amersham Pharmacia Biotech, Inc.) 0.1%non-fat dry milk and 25 nM [³H₂]Compound A (13.4 Ci/mmole), ±testcompound. After incubation for ˜16 h at 15° C. with shaking, the assayplates were counted in a Packard Topcount. In this assay the K_(d) forCompound A for LXRβ is ˜10 nM.

Results:

Representative tested compounds of Formula I are ligands for human LXRαand/or human LXRβ, each having an IC₅₀≦1,800 nM for at least one of theLXRα receptor or the LXRβ receptor, and preferred tested compoundshaving an IC₅₀ of 300 nM or less for at least one of the LXRα receptoror the LXRβ receptor.

EXAMPLE 2

Transactivation Assay

Plasmids

Expression constructs were prepared by inserting the ligand bindingdomain (LBD) of human LXRα and LXRβ cDNAs adjacent to the yeast GAL4transcription factor DNA binding domain (DBD) in the mammalianexpression vector pcDNA3 to create pcDNA3-LXRα/GAL4 andpcDNA3-LXRβ/GAL4, respectively. The GAL4-responsive reporter construct,pUAS(5×)-tk-luc, contained 5 copies of the GAL4 response element placedadjacent to the thymidine kinase minimal promoter and the luciferasereporter gene. The transfection control vector, pEGPP-N1, contained theGreen Fluorescence Protein (GFP) gene under the regulation of thecytomegalovirus promoter.

Assay

HEK-293 cells were seeded at 40,000 cells/well in 96 well plates inDulbecco's modified Eagle medium (high glucose) containing 10% charcoalstripped fetal calf serum, 100 units/ml Penicillin G and 100 μg/mlStreptomycin sulfate at 37° C. in a humidified atmosphere of 5% CO₂.After 24 h, transfections were performed with Lipofectamine (Gibco-BRL,Gaithersburg, Md.) according to the instructions of the manufacturer. Ingeneral, transfection mixes contained 0.002 μg of LXRα/GAL4 or LXRβ/GAL4chimeric expression vectors, 0.02 μg of reporter vector pUAS(5×)-tk-lucand 0.034 μg of pEGFP-N1 vector as an internal control of transfectionefficiency. Compounds were characterized by incubation with transfectedcells for 48 h across a range of concentrations. Cell lysates wereprepared from washed cells using Cell Lysis Buffer (Promega) accordingto the manufacturer's directions. Luciferase activity in cell extractswas determined using Luciferase Assay Buffer (Promega) in a ML3000luminometer (Dynatech Laboratories). GFP expression was determined usingthe Tecan Spectrofluor Plus at excitation wavelength of 485 nm andemission at 535 nm. Luciferase activity was normalized to GFP expressionto account for any variation in efficiency of transfection.

Results with representative tested compounds of Formula I for LXRαtransactivation having an EC₅₀ of ≦5,500 nM for at least one of the LXRαreceptor or the LXRβ receptor, and preferred tested compounds having anEC₅₀ of 1,000 nM or less for at least one of the LXRα receptor or theLXRβ receptor.

EXAMPLE 3

To assess the relevant biological activity of the LXR agonists, certaincompounds were tested for their ability to increase cholesterol effluxfrom cultured human cells, as described by Sparrow et al., JBC volume277, pages 10021–10027, Mar. 22, 2002. Caco-2 cells, which are of humanorigin, were obtained from ATCC and grown in Opti-MEM (Gibco #51985-034)containing 10% FCS, non-essential amino acids (Gibco #11140-050), andvitamins (Gibco # 11120-052). Caco-2 cells were plated at 100,000cells/well in 48-well plates. After four days the cells had reachedconfluence, and were then labeled with ³H-cholesterol by incubation for24 hours in fresh growth media containing ³H-cholesterol (10 μCi/ml).Following labeling with ³H-cholesterol, cells were washed and incubatedan additional 24 hours in serum-free media containing 1 mg/ml BSA, toallow for equilibration of ³H-cholesterol with intracellularcholesterol. Cholesterol efflux was initiated by adding 10 μg/ml apoA-I,with or without compound, in serum-free medium. Compounds were added tocell culture medium from DMSO solutions, and control cells received anequivalent amount of DMSO, never exceeding 0.1%. After 24 hours, mediawere harvested and cells dissolved in 0.1 M NaOH. Media were brieflycentrifuged to remove non-adherent cells, and then aliquots of both thesupernatants and the dissolved cells were subjected to liquidscintillation spectrometry to determine radioactivity. Cholesterolefflux is expressed as a percentage, calculated as (³H-cholesterol inmedium/(³H-cholesterol in medium+³H-cholesterol in cells))×100.

Table 1 shows cholesterol efflux results for the compound made inExample 16. Results are given as mean and SEM of quadruplicateincubations.

TABLE 1 Compound % cholesterol concentration (nM) efflux p value 0 2.8 ±0.3 1 3.2 ± 0.3 p = NS 10 4.0 ± 0.2 p = 0.01 100 8.8 ± 0.7 p < 0.0011000 10.3 ± 0.3  p < 0.001 5000 6.6 ± 0.4 p < 0.001

Table 2 shows cholesterol efflux results the compound made in Example25. Results are given as mean and SEM of quadruplicate incubations.

TABLE 2 Compound % cholesterol concentration (nM) efflux p value 0 3.0 ±0.1  1 3.4 ± 0.3  p = NS 10 3.5 ± 0.09 p = NS 100 4.5 ± 0.09 p < 0.0021000 4.6 ± 0.09 p < 0.002 5000 5.2 ± 0.2  p < 0.002

EXAMPLE 4

Step 1: Preparation of2,4-dihydroxy-3-propyl-1′,1′,1′-trifluoroacetophenone.

A solution of 2-propylresorcinol (5.0 grams) and trifluoroaceticanhydride (9.6 mL) in 1,2-dichloroethane (30.0 mL) was treated withaluminum chloride (4.38 grams). This mixture was stirred overnight. Thereaction mixture was partitioned between methylene chloride and water.The organic phase was dried over sodium sulfate and filtered. Thesolvent was evaporated and the resulting solid was recrystallized frommethylene chloride and cyclohexane (1:1) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.59 (d, 1H), 6.24 (d, 1H), 5.92 (s,1H), 2.63 (t, 2H), 1.74 (s, 1H), 1.58 (m, 2H), 0.98 (t, 3H).

Step 2: Preparation of3-trifluoromethyl-7-propyl-6-hydroxybenzisoxazole.

A mixture of 2,4-dihydroxy-3-propyl-1′,1′,1′-trifluoroacetophenone (2.5grams), sodium acetate (4.18 grams), hydroxylamine hydrochloride (3.59grams) and methanol (80 mL) was heated under reflux overnight. Thesolvent was then evaporated and the resulting solid was partitionedbetween ethyl acetate and pH 7 buffer. The organic phase was separatedand washed with brine. The organic phase was dried over sodium sulfateand the solvent was evaporated to give an oil. The oil was thendissolved in acetic anhydride. The solution was stirred for two hours,then the acetic anhydride was evaporated in vacuo. The residue waspartitioned between ethyl acetate and pH 7 buffer and the organic phasewas dried over sodium sulfate. The organic phase was evaporated to givean oil. The oil was dissolved in pyridine and refluxed overnight. Thesolvent was evaporated in vacuo to give an oil which was chromatographedon silica gel using ethyl acetate and hexane (1:4) to give the titlecompound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.46 (d, 1H), 6.92 (d, 1H), 5.42 (bs,1H), 2.89 (t, 2H), 1.74 (m, 2H), 0.98 (t, 3H).

EXAMPLE 5

Preparation of 6-hydroxy-3-neopentyl-7-propyl-1,2-benzisoxazole.

1-(2,4-dihydroxy-3-propylphenyl)-3,3-dimethylbutan-1-one (200 grams, 0.8mole), prepared as in Example 4 Step 1 from 3,3-dimethylbutanoic acidanhydride, was converted to6-hydroxy-3-neopentyl-7-propyl-1,2-benzisoxazole, as described inExample 4 Step 2, using hydroxylamine hydrochloride (278 grams, 4 mole)and sodium acetate (320 grams) and refluxing in methanol (2.5 L). Asecond addition of hydroxylamine hydrochloride (106 grams, 1.5 mole) andsodium acetate (250 grams) was made after 18 hours at reflux followed byfurther heating under reflux for a total of 36 hours. After isolation ofthe oxime, as described in Example 4 Step 2, the crude material waspurified by crystallization from hexanes. Conversion to the oximeacetate was accomplished by dissolving in acetic anhydride, as describedin Example 4 Step 2. Full conversion required 18 hours for this case.Ring closure in pyridine, as in Example 4 Step 2, yielded a dark oil.The crude product was eluted from silica gel with methylene chloride.The resulting oil was crystallized from hexanes:ether to yield the titlecompound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.33 (d, 1H, J=8.5 Hz), 6.81 (d, 1H,J=8.5 Hz), 5.07 (brd, 1H), 2.89 (collapsed dd, 2H), 1.77 (sect, 2H,J=7.5 Hz), 1.08 (s, 9H), 1.04 (t, 3H, J=7.3 Hz).

EXAMPLE 6

Step 1: Preparation of 2,4-dihydroxy-3-allylbenzophenone.

Commercially available 4-allyloxy-2-hydroxybenzophenone (15 grams) wasrearranged by heating under reflux in ortho-dichlorobenzene (60 mL) for26 hours. The product was isolated by dilution of the reaction mixturewith 5 volumes hexanes to give the title compound.

Selected Signals: ¹H NMR (CDCl₃); δ 7.62–7.59 (m, 2H), 7.56–7.52 (m,2H), 7.49–7.44 (m, 2H), 7.40 (d, 1H, J=8.9 Hz), 6.34 (d, 1H, J=8.8 Hz),6.02 (ddt, 1H, J=17.21, 10.1, 6.2 Hz), 5.72 (s, 1H, phenol OH),5.14–5.24 (m, 2H), 3.53 (d with fine splitting, 2H, J=6.2 Hz).

Step 2: Preparation of 2,4-dihydroxy-3-propylbenzophenone.

A solution of 2,4-dihydroxy-3-(2-propenyl)benzophenone (3 grams) wasreduced under ˜1 atmosphere of H₂ in ethyl acetate (100 mL) over 10%Pd/C catalyst (0.3 grams) for 3 hours. The product was purified bycrystallization from methanol/water to give the title compound.

Selected Signals: ¹H NMR (CDCl₃); δ 7.61–7.59 (m, 2H), 7.55–7.51 (m,1H), 7.48–7.44 (m, 2H), 7.33 (d, 1H, J=8.8 Hz), 6.29 (d, 1H, J=8.8 Hz),5.51 (s, 1H, phenol OH), 2.66 (dd, 2H, J=7.6, 9.3 Hz), 1.61 (sext, 2H,J=7.7 Hz), 0.99 (t, 3H, J=7.3 Hz).

Step 3: Preparation of 6-hydroxy-7-propyl-3-phenylbenzisoxazole.

The 2,4-dihydroxy-3-propylbenzophenone (2.5 grams, 9.8 mmol) wasconverted to the oxime with hydroxylamine hydrochloride (2.7 grams, 39mmol) and sodium acetate (3.21 grams, 39 mmol), as described in Example4 Step 2. The oxime was purified by elution from a silica gel columnwith 97:3 toluene:ethyl acetate. The product oxime was further treated,as in Example 4 Step 2, with acetic anhydride (15 mL) and subsequentlyheated under reflux in pyridine (15 mL).

The cooled reaction mixture was poured into 2 N hydrochloric acid andethyl acetate. The aqueous phase was extracted with ethyl acetate andwashed with saturated aqueous sodium bicarbonate, followed by saturatedaqueous sodium chloride. The ethyl acetate extracts were dried oversodium sulfate and reduced in vacuo. The residue was taken up inrefluxing toluene (50 mL) and cooled to RT to give the title compound.

Selected Signals: ¹H NMR (CDCl₃); δ 7.92–7.89 (m, 2H), 7.57 (d, 1H,J=8.5 Hz), 7.55–7.49 (m, 3H), 6.86 (d, 1H, J=8.6 Hz), 5.14 (s, 1H,phenol OH), 2.90 (dd, 2H, J=8.9, 7.6 Hz), 1.76 (sext, 2H, J=7.5 Hz),1.01 (t, 3H, J=7.3 Hz). MS CI NH₃ M+1 254.1.

EXAMPLE 7

Preparation of7-propyl-3-(trifluoromethyl)-6-(3-bromopropyloxy)-1,2-benzisoxazole.

To a DMF solution (50 mL) of6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole as prepared inExample 4 step 2 (5 grams, 20.4 mmol) was added 1,3-dibromopropane (10mL, 98.5 mmol), followed by cesium carbonate (10 grams, 30.7 mmol). Themixture was stirred at room temperature overnight. After aqueous etherwork-up and silica gel chromatography (hexanes: 2.5% ethyl acetate), thetitle compound was obtained.

Selected Signals: ¹H NMR (CDCl₃); δ 7.59 (d, 2H, J=8.8 Hz), 7.10 (d, 2H,J=8.8 Hz), 4.27 (t, 2H, J=5.8 Hz), 3.66 (t, 2H, J=6.4 Hz), 2.93 (t, 2H,J=7.5 Hz), 2.41 (pent, 2 H, J=6.0 Hz), 1.72 (sext, 2H, J=7.5 Hz), 0.99(t, 3H, J=7.5 Hz).

EXAMPLE 8

Preparation of7-propyl-3-(trifluoromethyl)-6-(4-bromobutyloxy)-1,2-benzisoxazole.

To a DMF solution (50 mL) of6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole as prepared inExample 4 step 2 (6.5 gram, 26.5 mmol) was added 1,4-dibromobutane (16mL, 133 mmol), followed by cesium carbonate (9.1 grams, 27.8 mmol). Themixture was stirred at room temperature overnight. After aqueous/etherwork-up and silica gel chromatography (hexanes: 2.5% ethyl acetate), thetitle compound was obtained.

Selected Signals: ¹H NMR (CDCl₃); δ 7.54 (d, 1H, J=8.7 Hz), 7.04 (d, 1H,J=8.7 Hz), 4.14 (t, 2H, J=5.9 Hz), 3.52 (t, 2H, J=6.6 Hz), 2.91(collapsed dd, 2H, J=7.5 Hz), 2.1 (m, 2H), 2.03 (m, 2H), 1.69 (sext, 2H,J=7.5 Hz), 0.966 (t, 3H, J=7.4 Hz). MS ESI M+1 380/382 isotope doublet.

EXAMPLE 9

Preparation of7-propyl-3-neopentyl-6-(3-bromopropyloxy)-1,2-benzisoxazole.

7-propyl-3-neopentyl-6-(3-bromopropyloxy)-1,2-benzisoxazole was preparedfrom 7-propyl-3-neopentyl-1,2-benzisoxazole as for Example 7 above.

Selected Signals: ¹H NMR (CDCl₃); δ 7.06 (d, 1H, J=8.8 Hz), 6.53 (d, 1H,J=8.5 Hz), 3.61 (t, 2H, J=5.9 Hz), 3.08 (t, 2H, J=6.4 Hz), 2.92(collapsed dd, 2H, J=7.5 Hz), 2.82 (t, 2H, J=6.3 Hz), 2.64 (s, 2H), 1.70(m, 2H, J=6.3 Hz), 0.946 (s, 9H), 0.884 (t, 3H, J=7.3 Hz).

EXAMPLE 10

Preparation of1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-pyrrolidine-2,5-dione.

Pyrrolidine-2,5-dione (17 mg, 0.172 mmol) and7-propyl-3-neopentyl-6-(3-bromopropyloxy)-1,2-benzisoxazole, fromExample 9 above, (42 mg, 0.114 mmol) were combined in DMF (7 ml) withCs₂CO₃ (56 mg, 0.17 mmol) at room temperature. The mixture was stirred18 hours. The mixture was diluted with 2 ml H₂O and acidified with TFA.The resulting mixture was purified by elution from a RP-18 reversedphase HPLC column with a 90:10 to 0:100 H₂O:CH₃CN gradient to yield1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione.

Selected Signals: ¹H NMR (400 MHz; CD₃OD) δ 7.51 (d, 1H, J=8.7 Hz), 7.03(d, 1H, J=8.8 Hz), 4.11 (t, 2H, J=6.0 Hz), 3.74 (t, 2H, J=7.0 Hz), 2.89(collapsed dd, 2H, J=7.6 Hz), 2.82 (s, 2H), 2.68 (s, 4H), 2.07 (pent,2H, J=6.8 Hz), 1.70 (sext, 2H, J=7.6 Hz), 1.03 (2, 9H), 0.971 (t, 3H,J=7.3 Hz).

EXAMPLE 11

Preparation of1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione.

1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-pyrrolidine-2,5-dionewas prepared as for Example 10 from pyrrolidine-2,5-dione and thebromide from Example 7. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; D₆-Benzene) δ 7.13 (d, 1H, Jobscured), 6.41 (d, 1H, J=8.8 Hz), 3.41 (2 overlapping triplets, 4 H,J=6.4, 6.1 Hz), 2.88 (collapsed dd, 2H), 1.74 (pent, 2H, J=7.2 Hz), 1.69(sext, 2H, J=7.4 Hz), 1.62 (s, 4H), 0.93 (t, 3H, J=7.4 Hz).

EXAMPLE 12

Preparation of2-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1H-isoindole-1,3(2H)-dione.

2-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1H-isoindole-1,3(2H)-dionewas prepared as for Example 10 from phthalimide and the bromide fromExample 9. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CD₃OD) δ 7.84–7.81 (m, 2H); 7.80–7.77(m, 2H); 7.50 (d, 1H, J=8.8 Hz); 7.03 (d, 1H, J=8.8 Hz); 4.17 (t, 2H,J=5.6 Hz); 3.94 (t, 2H, 6.6 Hz); 2.81 (s, 2H); 2.74 (t, 2H, J=7.6 Hz);2.21 (pentet, 2H, J=6.2 Hz); 1.63 (sextet, 2H, J=7.5 Hz); 1.02 (s, 9H);0.91 (t, 3H, J=7.2 Hz).

EXAMPLE 13

Preparation of3,3-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione.

3,3-Dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dionewas prepared as for Example 10 from 3,3-dimethylpyrrolidine-2,5-dioneand the bromide from Example 7. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.55 (d, 1H, J=9.0 Hz), 7.02(d, 1H, J=8.5 Hz), 4.09 (t, 2H, J=6.2 Hz), 3.74 (t, 2H, J=7.0 Hz), 2.94(t, 2H, J=7.5 Hz), 2.56 (s, 2H), 2.14 (pent, 2H, J=6.8 Hz), 1.72 (sext,2H, J=7.3 Hz), 1.32 (s, 6H), 0.98 (t, 3H, J=7.2 Hz).

EXAMPLE 14

Preparation of3-methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione.

3-Methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dionewas prepared as for Example 10 from3-methyl-3-phenylpyrrolidine-2,5-dione and the bromide from Example 7.After aqueous work-up and silica gel chromatography, the title compoundwas obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.55 (d, 1H, J=8.8 Hz);7.35–7.27 (m, 5H); 6.99 (d, 1H, J=8.8 Hz); 4.10 (t, 2H, J=6.2); 3.84(td, 2H, J₁=7.3 Hz, J₂=1.2 Hz); 3.16 (d, 1H, J=18.4 Hz); 2.94 (t, 2H,J=7.4 Hz); 2.88 (d, 1H, J=18.4 Hz); 2.20 (pentet, 2H, J=6.6 Hz); 1.73(sextet, 2H, J=7.5 Hz); 1.73 (s, 3H); 0.99 (t, 3H, J=7.4 Hz).

EXAMPLE 15

Preparation of3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione.

3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dionewas prepared as for Example 10 from thiazolidine-2,4-dione and thebromide from Example 9. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; C₆D₆) δ 7.07 (d, 1H, J=8.4 Hz); 6.54(d, 1H, J=8.4 Hz); 3.50 (t, 2H, J=5.8 Hz); 3.45 (t, 2H, J=7.2 Hz); 3.02(t, 2H, J=7.6 Hz); 2.75 (s, 2H); 2.63 (s, 2H); 1.80 (sextet, 2H, J=7.5);1.70 (pentet, 2H, J=7.0 Hz); 0.99 (t, 3H, J=7.4 Hz); 0.94 (s, 9H).

EXAMPLE 16

Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione.

3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dionewas prepared as for Example 10 from thiazolidine-2,4-dione and thebromide from Example 7. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; C₆D₆) δ 6.34 (d, 1H, J=8.8 Hz); 3.39(t, 2H, J=7.2 Hz); 3.29 (t, 2H, J=5.8 Hz); 2.86 (t, 2H, J=7.6 Hz); 2.71(s, 2H); 1.68 (sextet, 2H, J=7.5 Hz); 1.62 (pentet, 2H, J=6.5 Hz); 0.93(t, 3H, J=7.4 Hz).

EXAMPLE 17

Preparation of5,5-dimethyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione.

5,5-Dimethyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dionewas prepared as for Example 10 from 5,5-dimethylthiazolidine-2,4-dioneand the bromide from Example 9. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; C₆D₆) δ 7.05 (d, 1H, J=8.4 Hz); 6.54(d, 1H, 8.8 Hz); 3.57 (t, 2H, J=4.0 Hz); 3.50 (t, 2H, J=6.0 Hz); 3.05(t, 2H, J=7.6 Hz); 2.62 (s, 2H); 1.83–1.72 (m, 4H); 1.13 (s, 6H); 0.9(t, 3H, J=7.4 Hz); 0.92 (s, 9H).

EXAMPLE 18

Preparation of[2,4-dioxo-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3-thiazolidin-5-yl]aceticacid.

t-Butyl[2,4-dioxo-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3-thiazolidin-5-yl]acetatewas prepared as for Example 10 from t-butyl 1,3-thiazolidin-5-ylacetateand the bromide from Example 9. Ester cleavage with formic acid followedby evaporation of the solvent and silica gel chromatography yielded thetitle compound.

Selected Signals: ¹H NMR (400 MHz; CD₃OD) δ 7.52 (d, 1H, J=8.8 Hz); 7.04(d, 1H, J=8.8 Hz); 4.56 (dd, 1H, J₁=7.4 Hz, J₂=3.8 Hz); 4.13 (t, 2H,J=5.8 Hz); 3.86 (td, J₁=6.9 Hz, J₂=2.0 Hz); 3.15 (dd, 1H, J₁=17.8 Hz,J₂=2.0 Hz); 3.02 (dd, 1H, J₁=17.8 Hz, J₂=7.6 Hz); 2.89 (t, 2H, 4.9 Hz);2.82 (s, 2H); 2.13 (pentet, 2H, J=6.4 Hz); 1.69 (sextet, 2H, J=7.5 Hz);1.03 (s, 9H); 0.97 (t, 3H, J=7.4 Hz).

EXAMPLE 19

Preparation of3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from imidazolidine-2,4-dione and thebromide from Example 9. After aqueous ether work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.37 (d, 1H, J=8.8 Hz); 6.90(d, 2H, J=8.8 Hz); 5.93 (s, 1H); 4.11 (t, 2H, J=6.0 Hz); 3.98 (s, 2H);3.79 (t, 2H, J=7.0 Hz); 2.90 (t, 2H, J=7.6 Hz); 2.82 (s, 2H); 2.20(pentet, 2H, J=6.6 Hz); 1.72 (sextet, 2H, J=7.52 Hz); 1.06 (s, 9H); 1.01(t, 3H, J=7.4 Hz).

EXAMPLE 20

Preparation of3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from imidazolidine-2,4-dione and thebromide from Example 7. After aqueous ether work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.58 (d, 1H, J=9.0 Hz); 7.07(d, 1H, J=9.0 Hz); 5.30 (s, 1H); 4.17 (t, 2H, J=6.0 Hz); 4.01 (s, 2H);3.82 (t, 2H, J=7.0 Hz); 2.96 (t, 2H, J=7.5 Hz); 2.24 (pent, 2H, J=6.8Hz); 1.75 (sext, 2H, J=7.5 Hz); 1.01 (t, 3H, J=7.5 Hz).

EXAMPLE 21

Preparation of1-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

1-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from 1-methylimidazolidine-2,4-dione andthe bromide from Example 7. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.55 (d, 1H, J=8.5 Hz), 7.04(d, 1H, J=9.0 Hz), 4.13 (t, 2H, J=6.0 Hz), 3.87 (s, 2H), 3.76 (t, 2H,J=6.8 Hz), 3.00 (s, 3H), 2.92 (t, 2H, J=7.5 Hz), 2.19 (pent, 2H, J=6.5Hz), 1.71 (sext, 2H, J=7.5 Hz), 0.98 (t, 3H, J=7.5 Hz).

EXAMPLE 22

Preparation of5(R)-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

5(R)-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from 5(R)-methylimidazolidine-2,4-dioneand the bromide from Example 7. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (500 MHz; CD₃OD) δ 7.63 (d, 1H, J=9.0 Hz), 7.25(d, 1H, J=9.0 Hz), 4.18 (t, 2H, J=5.8 Hz), 4.09 (q, 1H, J=6.8 Hz), 3.73(td, J=7.0, 2.2 Hz), 2.95 (t, 2H, J=7.5 Hz), 2.15 (pent, 2H, J=6.0 Hz).1.73 (sext, 2H, J=7.5 Hz), 1.35 (d, 3H, J=7.0 Hz), 0.98 (t, 3H, J=7.5Hz).

EXAMPLE 23

Preparation of5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

5,5-Dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from 5,5-dimethylimidazolidine-2,4-dioneand the bromide from Example 7. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.57 (d, 1H, J=8.5 Hz), 7.06(d, 1H, J=8.5 Hz), 5.69 (s, 1H), 4.14 (t, 2H, J=6.0 Hz), 3.78 (t, 2H,J=7.0 Hz), 2.97 (t, 2H, J=7.5 Hz), 2.22 (pent, 2H, J=6.5 Hz), 1.75(sext, 2H, J=7.5 Hz), 1.45 (s, 6H), 1.01 (t, 3H, J=7.2 Hz). MS: m/z=414(M+H).

EXAMPLE 24

Preparation of1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

To solution of 2-aminopyridine (5.36 g) in CH₂Cl₂ (500 mL) at 0° C. wasadded chloroacetylisocyanate (5.9 mL). After several seconds, a thickwhite precipitate formed. After 5 minutes, 0.5 mL H₂O was added, and thesolvent was removed in vacuo to yield of3-chloroacetyl-1-(2-pyridyl)-urea. To 3-chloroacetyl-1-(2-pyridyl)-urea(1.26 g) in DMF (100 mL) was added Cs₂CO₃ (4.84 g) and1,3-dibromopropane (1.2 mL). The mixture was let stand overnight, andthen poured into 200 mL H₂O. The aqueous phase was extracted with 350mL. EtOAc, combined organic layers were washed with with brine, and thesolvent removed in vacuo to yield an off-white solid. This was slurriedin CH₂Cl₂ and vacuum filtered. The filtrate was adsorbed onto silicagel, and the solvent removed in vacuo to trap product for separation.The product was separated using column chromatography (30% EtOAc inhexanes) to yield 1-(3-bromopropyl)-3-(2-pyridyl)-imidazolidinedione asa white solid.

A mixture of 7-propyl-3-trifluoromethyl-6-hydroxy-1,2-benzisoxazole fromExample 7 (417 mg), 1-(3-bromopropyl)-3-(2-pyridyl)-imidazolidinedione(672 mg), and Cs₂CO₃ (867 mg) in DWF was allowed to react for 24 hoursat RT. The mixture was filtered, then separated by preparative HPLC toyield the title compound as a white solid.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 8.32 (dd, 1H, J1=4.5 Hz, 1.0Hz); 8.20 (d, 1H, J=8.5 Hz); 7.73–7.69 (m, 1H); 7.55 (d, 1H, J=8.5 Hz);7.07–7.04 (m, 2H); 4.55 (s, 2H); 4.18 (t, 2H, J=6.2 Hz); 3.88 (t, 2H,J=7.0 Hz); 2.91 (t, 2H, J=7.5 Hz); 2.26 (pentet, 2H, J=6.5 Hz); 1.71(sextet, 2H, J=7.5 Hz); 0.96 (t, 3H, J=7.2 Hz). MS: m/z=463 (M+H).

EXAMPLE 25

Preparation ofrac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from5-methyl-5-phenylimidazolidine-2,4-dione and the bromide from Example 7.After aqueous work-up and silica gel chromatography, the title compoundwas obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.49 (m, 2H), 7.39 (m, 3H),6.95 (d, 1H, J=8.8 Hz), 5.97 (brd, 1H), 4.08 (t, 2H, J=6.1 Hz), 3.79(dt, 2H, J=6.8, 2.5 Hz), 2.92 (t, 2H, J=7.5 Hz), 2.19 (m, 2H), 1.72(sext, 2H, J=7.5 Hz), 0.975 (t, 3H, J=7.5 Hz).

EXAMPLE 26

Preparation ofrac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from5-methyl-5-phenylimidazolidine-2,4-dione and the bromide from Example 9.After aqueous work-up and silica gel chromatography, the title compoundwas obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.50–7.48 (m, 2H); 7.41–7.31(m, 4H); 6.83 (d, 1H, J=8.8); 6.26 (s, 1H); 4.05 (t, 2H, J=6.0 Hz); 3.79(t, 2H, J=7.0 Hz); 2.88 (t, 2H, J=7.4 Hz); 2.82 (s, 2H); 2.18 (pentet,2H, J=6.5 Hz); 1.84 (s, 3H); 1.71 (sextet, 2H, J=7.6 Hz); 1.06 (s, 9H);0.98 (t, 3H, J=7.4 Hz).

EXAMPLE 27

Preparation ofrac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 10 from5-methyl-5-phenylimidazolidine-2,4-dione and the appropriate bromide.The bromide, 7-propyl-3-phenyl-6-(3-bromopropyloxy)-1,2-benzisoxazole,was prepared as for Example 7 using the7-propyl-3-phenyl-6-hydroxy-1,2-benzisoxazole prepared in Example 6.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.96–7.93 (m); 7.63 (d, 1H,J=8.8 Hz); 7.59–7.54 (m); 7.52–7.48 (m); 6.91 (d, 1H, J=8.8 Hz); 6.15(s, 1H); 4.09 (t, 2H, J=6.2 Hz); 3.80 (t, 2H, J=7.2 Hz); 2.94 (t, 2H,J=7.4 Hz); 2.20 (pentet, 2H, J=6.6 Hz); 1.84 (s, 2H); 1.75 (sextet, 2H,J=7.5 Hz); 1.00 (t, 3H, J=7.2 Hz).

EXAMPLE 28

Preparation ofrac-5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione.

rac-5-Methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dionewas prepared as for Example 10 from5-methyl-5-phenylimidazolidine-2,4-dione and the bromide from Example 8.After aqueous work-up and silica gel chromatography (toluene: 10%acetone), the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.52 (m, 3H), 7.4 (m, 3H),7.02 (d, 1H, J=9 Hz), 4.11 (t, 2H, J=5.6 Hz), 3.64 (t, 2H, J=6.5 Hz),2.89 (t, 2H, J=7.5 Hz), 1.86 (s, 3H), 1.68 (sext, 2H, J=7.5 Hz), 0.944(t, 3H, J=7.5 Hz).

EXAMPLE 29

Preparation ofrac-5-methyl-5-(3-carboxyphenyl)-3-(3-{[7-propyl-3-(trifluoromethyl-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

To a solution of 930 mg 3′-methylacetophenone in 5 mL anhydrous ethanolwas added 2.04 g NH₄HCO₃, 542 mg KCN, then 2.1 mL conc. NH₄OH. Themixture was stirred at 60° C. overnight. Addition of water and partialsolvent removal induced crystallization. The product was vacuum filteredand washed several times with water. The resultant white solid wasrecrystallized from MeOH to yield5-methyl-5-(3-methylphenyl)-imidazolidine-2,4-dione as a white solid. Asolution of 351 mg of the imidazolidinedione product, 822 mg KMnO₄ and1.44 g NaOH in 20 mL H₂O was heated to 95° C. for 2 hours, then allowedto cool to RT. Ethanol (5 mL) was added to decompose the remainingKMnO₄, and the mixture filtered, acidified, and left to stand overnight.The fine precipitate that formed was recovered by gravity filtration toyield, after drying in vacuo,5-methyl-5-(3-carboxyphenyl)-imidizalodine-2,4-dione as an off-whitesolid.

To a solution of 77 mg of5-methyl-5-(3-carboxyphenyl)-imidizalodine-2,4-dione in 5 mL DMF wasadded 112 mg Cs₂CO₃ and 45 μL benzyl bromide. The mixture was left toreact overnight, and then 1.0 mL H₂O was added, and the solublecomponents were separated by preparative scale HPLC to afford the benzylester of the above acid.

To 23 mg of the ester in 3 mL DMF was added 31.3 mg7-propyl-3-(trifluoromethyl)-6-(3-bromopropyloxy)-1,2-benzisoxazole, and38.9 mg Cs₂CO₃. The mixture was allowed to react overnight, and then 0.4mL H₂O was added. The soluble components were separated by preparativescale HPLC, to yield the benzyl ester of the desired product as a whitesolid. Reduction of this material in methanol using H₂ and PdOH/C wascomplete within an hour, and after purification by preparative HPLC, thetitle compound was obtained.

Selected Signals: ¹H NMR (500 MHz; CD₃OD) δ 8.16 (s, 1H), 7.89 (d, 1H,J=8.5 Hz), 7.74 (d, 1H, J=7.5 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.42 (t, 1H,J=8.0 Hz), 7.08 (s, 1H, J=9.0 Hz), 4.14–4.04 (m, 2H), 3.84–3.71 (m, 2H),2.88 (t, 2H, J=7.5 Hz), 2.19–2.13 (m, 2H), 1.77 (s, 3H), 1.69 (sext, 2H,J=7.3 Hz), 0.96 (t, 3H, J=7.5 Hz). MS: m/z=520 (M+H).

EXAMPLE 30

Preparation ofrac-5-methyl-5-(4-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

A mixture of 4-acetyl pyridine (3.0 mL), NH₄HCO₃ (7.73 g), KCN (2.16 g),and concentrated NH₄OH (8.2 mL) in EtOH (10.35 mL) was heated to 60° C.overnight under a reflux condenser. The reaction mixture was extractedwith ether, then acidified to pH 4.5 with concentrated HCl and extractedwith EtOAc. The combined organic extracts from the acidic extractionwere dried over Na₂SO₄. Solvent was removed in vacuo to yield crude5-methyl-5-(4-pyridyl)-imidazolidinedione as an off-white solid.

A mixture of crude rac-5-methyl-5-(4-pyridyl)-imidazolidinedione (29mg), 7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole(27 mg) from Example 7, and Cs₂CO₃ (71 mg) in DMF (3.0 mL) was allowedto react overnight. Water (0.4 mL) was added and the resulting mixtureseparated by HPLC to yield the title compound as a clear oil.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 8.84 (d, 2H, J=5.5 Hz), 8.07(d, 2H, 6.0 Hz), 7.56 (d, 1H, 8.5 Hz), 7.01 (d, 1H, J=9.0 Hz), 4.11 (t,2H, J=5.8 Hz), 4.02 (b), 3.83 (t, 2H, J=7.2 Hz), 2.94 (t, 2H, J=7.2 Hz),2.21 (pentet, 2H, J=6.8 Hz), 1.90 (s, 3H), 1.73 (sextet, 2H, J=7.5 Hz),0.99 (t, 3H, J=7.2 Hz). MS: m/z=477 (M+H).

EXAMPLE 31

Preparation ofrac-5-methyl-5-(3-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

rac-5-Methyl-5-(3-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 30 starting from 3-acetylpyridine.

Selected Signals: ¹H NMR (500 MHz; CD₃OD) δ 8.94 (s, 1H), 8.71 (d, 1H,J=5.5 Hz), 8.58 (dt, 1H, J=8.5, 1.8 Hz), 7.88 (dd, 1H, J=8.0, 5.5 Hz),7.60 (d, 1H, J=8.5 Hz); 7.18 (d, 1H, J=9.0 Hz), 4.18–4.10 (m, 2H),3.81–3.75 (m, 2H), 2.91 (t, 2H, J=7.5 Hz), 2.17 (pentet, 2H, J=6.0 Hz),1.83 (s, 3H), 1.71 (sextet, 2H, J=7.5 Hz), 0.96 (t, 3H, J=7.5 Hz). MS:m/z=477 (M+H).

EXAMPLE 32

Preparation ofrac-5-methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

rac-5-Methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 30 starting from 2-acetylpyridine.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 8.66 (d, 1H, J=5.0 Hz), 7.86(td, 1H, J=8.0,1.8 Hz), 7.82 (d, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.5 Hz),7.42–7.41 (m, 1H), 7.02 (d, 1H, J=9.0 Hz), 4.16–4.08 (m, 2H), 3.87–3.82(m, 2H), 2.91 (t, 2H, J=7.5 Hz), 2.22 (pent, 2H, J=6.8 Hz), 1.85 (s,3H), 1.71 (sext, 2H, J=7.5 Hz), 0.98 (t, 3H, J=7.2 Hz). MS: m/z=477(M+H).

EXAMPLE 33

Separation of the Active Enantiomer of5-Methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

The racemic product prepared in Example 32 was separated using chiralstationary phase HPLC (Chiracell AD column; 30% iPA in pentane) to yieldthe active enantiomer as the first eluting compound.

EXAMPLE 34

Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrimidin-2-ylimidazolidine-2,4-dione.

3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrimidin-2-ylimidazolidine-2,4-dionewas prepared as for Example 24 above starting from 2-aminopyrimidine.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 8.63 (d, 2H, J=5.0 Hz), 7.54(d, 1H, J=8.5 Hz), 7.10 (t, 1H, J=4.8 Hz), 7.04 (d, 1H, J=9.0 Hz), 4.54(s, 2H), 4.18 (t, 2H, J=6.0 Hz), 3.90 (t, 2H, J=7.0 Hz), 2.91 (t, 2H,J=7.5 Hz), 2.27 (pent, 2H, J=6.5 Hz), 1.70 (sext, 2H, J=7.5 Hz), 0.95(t, 3H, J=7.5 Hz). MS: m/z=464 (M+H).

EXAMPLE 35

Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dione.

3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dionewas prepared as for Example 24 above starting from 2-aminopyrazine.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 9.60 (s, 1H); 8.38 (s, 1H);8.31 (s, 1H); 7.57 (d, 1H, J=9.0 Hz); 7.07 (d, 1H, J=8.5 Hz); 4.52 (s,2H); 4.21 (t, 2H, J=6.0 Hz); 3.93 (t, 2H, J=7.0 Hz); 2.93 (t, 2H, J=7.5Hz); 2.30 (pentet, 2H, J=6.5 Hz); 1.73 (sextet, 2H, J=7.5 Hz); 0.98 (t,3H, J=7.2 Hz). MS: m/z=464 (M+H).

EXAMPLE 36

Preparation ofrac-3-[2,5-dioxo-4-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-4-yl]propanoicacid.

A mixture of 3-benzoylpropionic acid (2.26 g), NH₄HCO₃ (3.63 g), and KCN(1.03 g) in a solution of 5 mL EtOH and 4 mL conc. NH₄OH was heated to60 C in an oil bath under a reflux condenser overnight. Water was addedand the mixture extracted with ether, acidified with concentrated HCl,extracted with EtOAc and then CH₂Cl₂. The extracts of the acidifiedaqueous were reduced in vacuo to yield crude2,5-dioxo-4-phenylimidazolidin-4-yl]propanoic acid.

A mixture of7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole (54mg), crude 2,5-dioxo-4-phenylimidazolidin-4-yl]propanoic acid (56 mg),and Cs₂CO₃ (95 mg) in 3.0 mL DMF was allowed to react overnight. Afteraqueous workup, the mixture was separated by preparative scale TLC (40%EtOAc in hexanes with 1% MeOH added) to give the titled compound.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 8.25 (s, 1H); 7.58 (d, 1H,J=8.5 Hz); 7.54–7.52 Hz (m, 2H); 7.43–7.35 (m,4H); 7.06 (d, 1H, J=9.0Hz); 4.32 (td, 2H, J₁=6.2 Hz, J₂=1.3 Hz); 4.16 (t, 2H, J=6.0 Hz); 2.92(t, 2H, J=7.5 Hz); 2.53 (t, 2H, J=7.0 Hz); 2.45–2.35 (m, 2H); 2.18 (p,2H, J=6.5 Hz); 1.71 (sextet, 2H, 7.5 Hz); 0.97 (t, 3H, J=7.5 Hz).

EXAMPLE 37

Preparation of4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]butanoicacid.

A mixture of 5,5-dimethylhydantoin (5.25 g), 1-bromo-3-chloropropane(8.5 mL), and Cs₂CO₃ (20.78 g) in 40 mL DMF was allowed to reactovernight. The reaction was poured into 125 mL H₂O, extracted withether, and the combined extracts dried over MgSO₄. The crude extract wasfiltered, then reduced in vacuo to yield a clear oil. The residue waschromatographed (50% EtOAc in hexanes) to yield3-(3-chloropropyl)-5,5-dimethylimidazolidinedione as a white solid.

To a solution of 3-(3-chloropropyl)-5,5-dimethylimidazolidinedione (109mg), in DMF (5.0 mL) at 0 C was added 1.0 M lithium hexamethyldisilazide(0.64 mL, in hexanes). After 5 minutes, ethyl 4-bromobutyrate (0.23 mL)was added, and the mixture allowed to warm gradually to RT overnight.Water (10 mL) was added and the mixture extracted with ether. Combinedether extracts were dried over MgSO₄, filtered and reduced in vacuo. Theresidue was separated by HPLC to yield 1-alkylated product, ethyl4-[5,5-dimethyl-2,4-dioxo-3-(3-bromopropyl)imidazolidin-1-yl]butanoate,as a clear oil.

A mixture of the 1-alkylated product (45 mg),7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole fromExample 7 (36 mg), and Cs₂CO₃ (104 mg) in 4.0 mL DMF was allowed toreact overnight. The reaction mixture was filtered, then separated byHPLC to yield ethyl4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]butanoateas a clear oil. To a solution of 13 mg of the ethyl ester in 1.0 mL EtOHwas added 0.45 mL H₂O and 3 mg KOH. The mixture was allowed to reactovernight, then diluted to 4 mL with 50% aqueous CH₃CN. The solution wasseparated by preparative BPLC to yield the title compound.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.56 (d, 1H, J=9.0 Hz), 7.06(d, 1H, J=9.0 Hz), 4.13 (t, 2H, J=6.2 Hz), 3.77 (t, 2H, J=7.2 Hz), 3.36(t, 2H, J=7.5 Hz), 2.95 (t, 2H, J=7.5 Hz), 2.46 (t, 2H, J=7.2 Hz), 2.20(pent, 2H, J=6.8 Hz), 1.98 (pent, 2H, J=7.5 Hz), 1.74 (sext, 2H, J=7.5Hz), 1.42 (s, 6H), 0.99 (t, 3H, J=7.5 Hz). MS: m/z=500 (M+H).

EXAMPLE 38

Preparation of4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoicacid.

4-[5,5-Dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoicacid was prepared as for Example 37, substituting 5-bromovalerate forthe 4-bromobutyrate of Example 37.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.56 (d, 1H, J=9.0 Hz), 7.06(d, 1H, J=9.0 Hz), 4.13 (t, 2H, J=6.0 Hz), 3.77 (t, 2H, J=7.0 Hz), 3.30(t, 2H, J=7.0 Hz), 2.95 (t, 2H, J=7.0 Hz), 2.42 (t, 2H, J=6.8 Hz), 2.21(pent, 2H, J=6.8 Hz), 1.76–1.70 (m, 6H), 1.40 (s, 6H), 1.00 (t, 3H,J=7.5 Hz). MS: m/z=514 (M+H).

EXAMPLE 39

Preparation of1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one.

To a DMF solution (5 mL) of7-propyl-3-(trifluoromethyl)-6-(3-bromopropyloxy)-1,2-benzisoxazole asprepared in Example 7 (322 mg, 0.88 mmol), was added 2-imidazolidinone(320 mg, 3.52 mmol) and CsCO₃ (320 mg, 0.97 mmol) then stirred at roomtemperature overnight. After aqueous work-up and silica gelchromatography (hexanes: 70% ethyl acetate), the title compound wasobtained.

Selected Signals: ¹H NMR (CDCl₃) δ 7.57 (d, 1H, J=9 Hz), 7.08 (d, 1H,J=9 Hz), 4.28 (s, 1H) 4.18 (t, 2H, J=6.5 Hz), 3.49 (m, 2H), 3.47 (m,4H), 2.95 (t, 2H, J=7.5 Hz), 2.12 (m, 2H), 1.75 (m, 2H), 0.96 (t, 3H,J=7 Hz). MS: m/z=372 (M+H)

EXAMPLE 40

Preparation of methyl2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoate.

To a DMF solution (2 mL) of1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-oneas prepared in Example 39 (10 mg, 0.027 mmol), was added NaH (4.3 mg,1.08 mmol) and stirred at room temperature for 30 minutes. Methyl2-bromopropionate (27 mg, 0.16 mmol) was added and the mixture stirredfor another 3 hour. After aqueous work-up and silica gel chromatography(hexanes:70% ethyl acetate), the title compound was obtained.

Selected Signals: ¹H NMR (CDCl₃) δ 7.57 (d, 1H, J=9 Hz), 7.09 (d, 1H,J=9 Hz), 4.67 (q, 1H, J=7.5 & 14.5 Hz), 4.17 (t, 2H, J=7.5 Hz), 3.7 (s,3H), 3.39–3.51 (m, 6H), 2.94 (t, 2H, J=7.5 Hz), 2.10 (m, 2H), 1.75 (m,2H), 1.43 (d, 3H, J=7.5 Hz), 0.98 (t, 3H, J=7.0 Hz). MS: m/z=458 (M+H)

EXAMPLE 41

Preparation of2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoicacid.

To a MeOH solution (0.6 mL) of methyl2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoateas prepared in Example 40 (17.6 mg, 0.039 mmol), was added NaOH (0.6 mL,0.154 mmol) and the mixture stirred at room temperature overnight. Thereaction mixture was neutralized with 1N HCl and purified by preparativeHPLC and the title compound was obtained.

Selected Signals: ¹H NMR (CDCl₃) δ 7.57 (d, 1H, J=9 Hz), 7.09 (d, 1H,J=9 Hz), 4.67 (q, 1H, J=7.5 & 14.5 Hz), 4.17 (t, 2H, J=7.5 Hz),3.39–3.51 (m, 6H), 2.94 (t, 2H, J=7.5 Hz), 2.10 (m, 2H), 1.75 (m, 2H),1.43(d, 3H, J=7.5 Hz), 0.98 (t, 3H, J=7.0 Hz). MS: m/z=444 (M+H)

EXAMPLE 42

Preparation of1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

A mixture of imidazolidine-2,4-dione (5.01 g), Cs₂CO₃, and4-methoxybenzyl chloride (8.0 mL) in DMF (250 mL) was allowed to reactovernight. The reaction was added to 400 mL brine then extracted withether. The desired product precipitated from the ether, and wascollected by filtration to yield1-(4-methoxybenzyl)-imidazolidine-2,4-dione as a white solid.

A mixture of 1-(4-methoxybenzyl)-imidazolidine-2,4-dione (57 mg),7-propyl-3-trifluoromethyl-6-(3-bromopropyloxy)-1,2-benzisoxazole fromExample 7 (86 mg), and Cs₂CO₃ (146 mg) in DMF (4.0 mL) was allowed toreact overnight. Water was added and the mixture separated by HPLC toyield1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-3-(4-methoxybenzyl)-imidazolidine-2,4-dioneas a clear oil.

To a solution of this compound (39 mg) in a mixture of CH₃CN (5.4 mL)and H₂O (0.6 mL) was added ceric ammonium nitrate (210 mg) and theresultant solution was allowed to react overnight. The reaction wasdiluted with H₂O (9 mL), then extracted with EtOAc. The combined organiclayers were washed sequentially with saturated NaHCO₃, NaHSO₃, and withbrine and dried over Na₂SO₄. The crude extract was filtered and thesolvent removed in vacuo to yield a clear oil/white solid, which wasdissolved in 2:1 CH₃CN and separated by HPLC to yield the titlecompound.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 7.73 (s, 1H), 7.60 (d, 1H,J=9.0 Hz), 7.07 (d, 1H, J=8.5 Hz), 4.19 (t, 2H, J=6.0 Hz), 4.00 (s, 2H);3.66 (t, 2H, J=7.0 Hz), 2.95 (t, 2H, J=7.5 Hz), 2.18 (pent, 2H, J=6.8Hz), 1.74 (sext, 2H, J=7.5 Hz), 1.00 (t, 3H, J=7.2 Hz). MS: m/z=386(M+H).

EXAMPLE 43

Preparation of5,5-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione.

5,5-Dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dionewas prepared as for Example 42 starting from5,5-dimethylimidazolidinedione.

Selected Signals: ¹H NMR (500 MHz; CDCl₃) δ 8.54 (s, 1H), 7.60 (d, 1H,J=9.0 Hz), 7.08 (d, 1H, J=8.5 Hz), 4.19 (t, 2H, J=6.0 Hz), 3.52 (t, 2H,J=7.5 Hz), 2.96 (t, 2H, J=7.8 Hz), 2.27 (pent, 2H, J=7.2 Hz), 1.75(sext, 2H, J=7.5 Hz), 1.47 (s, 6H), 1.02 (t, 3H, J=7.5 Hz). MS: m/z=414(M+H).

EXAMPLE 44

Step 1: Preparation of cis2-({tert-butyl(dimethyl)silyloxy}methyl)cyclohexanol.

To a solution of ethyl cis-2-hydroxy-1-cyclohexanecarboxylate (2 g,11.62 mmol) in EtOH (70 mL) was added NaBH₄ (2.2 g, 11.62 mmol) inportions at 0° C. The mixture was stirred at room temperature overnight.The reaction mixture was partitioned between ethyl acetate and water.The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The solvent was evaporated in vacuo to give the diol.

tert-Butyldimethylsilyl chloride (1.7 g, 11.07 mmol) in dry THF (11 mL)was added dropwise to a mixture of the diol (1.2 g, 9.23 mmol) andimidazole (1.56 g, 22.15 mmol) in dry THF (14 mL) at 0° C. The reactionmixture was stirred at room temperature 72 hrs. Solvent was evaporatedand the residue dissolved in ethyl ether, washed with water three times,dried over Na₂SO₄ and filtered. The solvent was evaporated in vacuo. Theresidue was purified by chromatography on silica gel using acetone andhexane (1:99) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 4.056 (m, 1H), 3.735 (dd, 1H), 3.671(dd, 1H), 1.773–1.183 (m, 9H), 0.855 (s, 9H), 0.023 (s, 6H).

Step 2: Preparation of6-{[cis-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole.

A mixture of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole(730 mg, 2.98 mmol),2-({tert-butyl(dimethyl)silyloxy}methyl)-cyclohexanol (800 mg, 3.28mmol) from this Example step 1, and triphenylphosphine (1.02 g, 3.874mmol) was dissolved in dry benzenes (16 mL). Diisopropylazodicarboxylate(0.78 mL, 3.874 mmol) was added dropwise. The reaction mixture wasstirred at room temperature overnight. The solvent was evaporated invacuo and the residue purified by chromatography on silica gel usingacetone and hexane (1:99) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.53 (d, 1H, J=9 Hz), 7.182 (d, 1H,J=8.9 Hz), 4.374 (m, 4H), 3.825 (m, 1H), 3.684 (m, 1H), 2.930 (t, 2H,J=7.5 Hz, 7.6 Hz), 2.146–1.327 (m, 11H), 1.004 (t, 3H, J=7.3 Hz, 7.4Hz), 0.898 (d, 9H, J=21.3 Hz), 0.037 (t, 6H, J=29.5 Hz, 37.8 Hz).

Step 3: Preparation of6-{[cis-2-(hydroxymethyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole.

To a solution of6-{[(1S,2S)-2-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole(550 mg, 1.17 mmol), from this Example step 2, in dry THF (17 ml) wasadded tetrabutylammonium fluoride (1M THF, 1.75 mL, 1.75 mmol) at 0° C.The reaction mixture was stirred at room temperature for two hours.Saturated NaHCO₃ was added. The mixture was extracted with ethyl acetatethree times and the combined organic layers washed with brine, driedover Na₂CO₃ and filtered. The solvent was evaporated in vacuo. Theresidue was purified by chromatography on silica gel using ethyl acetateand hexane (20:80) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.551 (d, 1H, J=9 Hz), 7.167 (d, 1H,J=8.9 Hz), 4.351 (m, 4H), 3.792 (m, 2H), 2.922 (t, 2H, J=7.6 Hz, 7.8Hz), 2.138–1.590 (m, 8H), 1.438–1.316 (m, 4H), 0.994 (t, 3H, J=7.3 Hz,7.3 Hz).

Step 4: Preparation ofcis(2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methylmethanesulfonate.

To a solution of6-{[cis-2-(hydroxymethyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole(388 mg, 1.09 mmol), from this Example step 3, in CH₂Cl₂ (11 mL) wasadded Et₃N (0.230 ml, 1.635 mmol) at 0° C., followed by methanesulfonylchloride (0.093 mL, 1.2 mmol). The reaction mixture was stirred from 0°C. to room temperature for four hours. The mixture was diluted withCH₂Cl₂, washed with 5% HCl, followed by H₂O then NaHCO₃. Organicextracts were dried over NaSO₄ and filtered. The solvent was evaporatedin vacuo to give title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.555 (d, 1H, J=8.7 Hz), 7.103 (d,1H, J=8.9 Hz), 4.447 (m, 1H), 4.33 (m, 2H), 2.934 (s, 3H), 2.913 (t, 2H,J=7.5 Hz, 7.8 Hz), 2.197–1.994 (m, 4H), 1.841–1.335 (m, 7H), 0.985 (t,3H, J=7.4 Hz, 7.5 Hz). MS: m/z=436.1 (M+1)

Step 5: Preparation of1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione.

cis-(2-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methylmethanesulfonate (50 mg, 0.115 mmol from this Example step 4),5,6-dihydrouracil (39.4 mg, 0.345 mmol) and Cs₂CO₃ (150 mg, 0.46 mmol)were dissolved in dry DMF (1 mL) and stirred at room temperature 72 hrs.The reaction mixture was diluted with water and partitioned betweenethyl acetate and water. The combined organic extracts were washed withwater and brine, dried over Na₂SO₄ and filtered. The solvent wasevaporated in vacuo. The residue was purified by preparative TLC usingethyl acetate and hexane (20:80) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.536 (d, 1H, J=8.9 Hz), 7.12 (d, 1H,J=9 Hz), 4.298 (m, 1H), 4.117 (m, 1H), 3.798 (m, 1H), 3.329 (m, 2H),2.936 (m, 2H), 2.658 (m, 2H), 2.280(m, 1H), 2.051–1.622 (m, 5H),1.369–1.206 (m, 4H), 0.990 (t, 3H, J=7.3 Hz, 7.4 Hz). MS: m/z=454.2(M+1)

EXAMPLE 45

Step 1: Preparation of(trans-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methylmethanesulfonate.

(trans-2-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl methanesulfonate was prepared as for Example 44 Steps 1 through 4starting from ethyl cis-2-hydroxycyclopentanecarboxylate.

Selected Signals: ¹H NMR (CDCl₃) δ 7.57 (d, 1H, J=8.7 Hz), 7.12 (d, 1H,J=8.7 Hz), 4.8 (m, 1H), 4.27 (m, 2H), 30336 (s, 3H), 2.896 (t, 2H, J=7.3Hz, 7.6 Hz), 2.197–1.994 (m, 4H), 1.841–1.335 (m, 7H), 0.985 (t, 3H,J=7.3 Hz, 7.4 Hz). MS: m/z=422.2 (m+1)

Step 2: Preparation of1-[trans-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione.

1-[((1R,2S)-2-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl]dihydropyrimidine-2,4(1H,3H)-dionewas prepared from the mesylate of this Example step 1 as for Example 44Step 5. The product was purified by preparative TLC using ethyl acetateand hexane (50:50) to give title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.537 (d, 1H, J=8.9 Hz), 7.056 (d,1H, J=8.9 Hz), 4.764 (m, 1H), 3.685 (m, 1H), 3.826 (m, 1H), 3.288 (m,2H), 2.873 (t, 2H, J=7.3 Hz, 7.3 Hz). MS: m/z=440.2 (M+1)

EXAMPLE 46

Step 1: Preparation of7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yltrifluoromethanesulfonate.

To a solution of6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (500 mg, 2.04mmol) in dry CH₂Cl₂ was added pyridine (0.82 mL, 10.2 mmol) at 0° C.under N₂. Tf₂O was then added dropwise to the reaction mixture and theresulting mixture stirred for 30 min. 1N NaOH was added and the mixtureextracted with CH₂Cl₂. Combined organic extracts were washed with brine,dried over Na₂SO₄ and the solvent evaporated in vacuo. The residue waspurified by chromatography on silica gel using ethyl acetate and hexane(10:90) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.75 (d, 1H, J=8.9 Hz), 7.43 (d, 1H,J=8.7 Hz), 3.07 (t, 2H), 1.85 (m, 2H), 1.06 (t, 3H, J=7.3 Hz, 7.3 Hz).

Step 2: Preparation of (but-3-enyloxy)(tert-butyl)dimethylsilane.

To a solution of but-3-en-1-ol (2.39 mL, 27.73 mmol) in DMF was addedimidazole (3.78 g, 55.46 mmol), and tert-butyldimethylsilyl chloride(6.3 g, 41.59 mmol). The mixture was stirred at room temperatureovernight. Saturated NH₄Cl was added and the mixture was extracted withethyl acetate three times. Combined organic extracts were washed twicewith water and brine then dried over Na₂SO₄. The solvent was evaporatedin vacuo to give title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 5.84 (m, 1H), 5.07 (m, 2H), 3.68 (t,2H, J=6.7 Hz, 6.8 Hz), 2.31 (m, 2H), 0.92 (t, 9H), 0.08 (t, 61).

Step 3: Preparation of6-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole.

To a solution of (but-3-enyloxy)(tert-butyl)dimethylsilane, from thisExample step 2, (148 mg, 0.79 mmol) in dry THF (0.25 mL) was added 9-BBN(0.5M 1.75 mL, 0.88 mmol) at 0° C. under N₂. The mixture was stirred for5 hours, then added to a mixture of7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yltrifluoromethanesulfonate, as prepared in this Example step 1, (300 mg,0.79 mmol), K₂CO₃ (220 mg, 1.59 mmol), anddichlorobis(triphenylphosphene) palladium (32.5 mg, 0.039 mmol) in DMF(3 mL) under N₂ in a sealed tube. The mixture was stirred overnight at55° C. The reaction mixture was partitioned between ethyl acetate andwater. Combined organic extracts were washed with water twice and brineand then dried over Na₂SO₄. The solvent was evaporated in vacuo. Theresidue was purified by chromatography on silica gel using ethyl acetateand hexane (1:30) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.56 (d, 1H, J=8.2 Hz), 7.29 (d, 1H,J=8.3 Hz), 3.68 (t, 2H, J=6.2 Hz, 5.9 Hz), 2.98 (t, 2H, J=8 Hz, 7.9 Hz),2.83 (t, 2H, J=7.5 Hz, 8.1 Hz), 1.72 (m, 6H), 1.06 (t, 3H). 0.916 (s,9H), 0.072 (s, 6H).

Step 4: Preparation of4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butan-1-ol.

To a solution of6-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole,from this Example step 3, (2.8 g, 6.7 mmol) in dry THF (75 mL) was addedtetrabutylammonium fluoride (1.0M 10.1 mL, 10.1 mmol) at 0° C. Themixture was stirred at room temperature for 2 hours. Saturated NaHCO₃was added and the mixture was extracted with ethyl acetate 3 times.Combined organic extracts were washed with brine and dried over Na₂SO₄.The solvent was evaporated in vacuo. The residue was purified bychromatography on silica gel using ethyl acetate and hexane (20:80) togive the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.56 (d, 1H, J=8.2 Hz), 7.3 (d, 1H,J=8.0 Hz), 3.72 (m, 2H), 2.98 (t, 2H, J=7.8 Hz, 8 Hz), 2.85 (t, 2H,J=7.1 Hz, 8 Hz), 1.73 (m, 6H), 1.05 (t, 3H, J=7.3 Hz, J=Hz).

Step 5: Preparation of4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butylmethanesulfonate.

To a solution of4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butan-1-ol, fromthis Example step 4, in CH₂Cl₂ (25 mL) was added Et₃N (0.42 mL, 2.99mmol) and methanesulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. Themixture was stirred from 0° C. to room temperature for 2 hours. 0.5N HClwas added and the mixture extracted 3 times with CH₂Cl₂. Combinedorganic extracts were washed with water and brine then dried overNa₂SO₄. The solvent was evaporated in vacuo to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.58 (d, 1H J=8.2 Hz), 7.29 (d, 1HJ=8.2 Hz), 4.3 (t, 2H, J=6.1 Hz, 6.4 Hz), 3.037 (s, 3H), 2.98 (t, 2H),2.87(t, 2H, J=8 Hz, 7.5 Hz), 1.88 (m, 2H), 1.78 (m, 4H), 1.06 (t, 2H,J=7.3 Hz, 7.3 Hz).

Step 6: Preparation of1-{4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl}dihydropyrimidine-2,4(1H,3H)-dione.

A mixture of 4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butylmethanesulfonate (60 mg, 0.16 mmol), from this Example step 5, Cs₂CO₃(206 mg, 0.63 mmol) and 5,6-dihydrouracil (54.2 mg, 0.48 mmol) in dryDMF (1.5 mL) was stirred at room temperature overnight. The reactionmixture was partitioned between ethyl acetate and water. Combinedorganic extracts were washed with water and brine, dried over Na₂SO₄ andthe solvent evaporated in vacuo. The residue was purified by preparativeTLC using ethyl acetate to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.55 (d, 1H J=8.2 Hz), 7.28 (d, 1HJ=8.2 Hz), 5.704 (s, 1H), 3.8 (t, 2H, J=6.9 Hz, 6.3 Hz), 3.42 (m, 2H,)2.96 (t, 2H), 2.832 (t, 2H, J=8.0 Hz, 7.1 Hz), 2.741 (t, 2H, J=6.7 Hz,6.8 Hz), 1.68 (m, 6H), 1.044 (t, 2H, J=7.3, 7.3 Hz). MS: m/z=398.2 (M+1)

EXAMPLE 47

Step 1: Preparation of 5-phenyldihydropyrimidine-2,4(1H,3H)-dione.

A mixture of D-(−)-alpha-phenylglycine ethyl ester HCl (200 mg, 0.93mmol) and potassium cyanate (92.7 mg, 1.14 mmol) in water (15 mL) washeated at reflux overnight. Upon cooling to room temperature, theproduct precipitated from the reaction mixture. The product wascollected by filtration and dried for use without purification.

Selected Signals: ¹H NMR (CD₃OD) δ 7.3 (m, 5H), 3.9 (m, 1H), 3.61 (m,1H), 3.53 (m, 1H).

Step 2: Preparation of5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione.

A mixture of6-(3-chloropropoxy)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole,prepared as for Example 7 from bromochloropropane, (36 mg, 0.12 mmol),5-phenyldihydropyrimidine-2,4(1H,3H)-dione, from this Example step 1,(42.5 mg, 0.22 mmol), Cs₂CO₃ (145.7 mg, 0.45 mmol) and KI (9.3 mg, 0.056mmol) in dry DMF was stirred at room temperature overnight. The reactionmixture was diluted with water and partitioned between ethyl acetate andwater. Combined organic extracts were washed with water and brine, driedover Na₂SO₄ and the solvent evaporated in vacuo. The product waspurified by HPLC using 30% to 70% gradient CH₃CN:H₂O).

Selected Signals: ¹H NMR (CDCl₃) δ 7.55 (d, 1H, J=8.7 Hz), 7.36 (m, 5H)7.04 (d, 1H, J=8.7 Hz), 5.722 (s, 1H), 4.13 (m, 4H), 3.93 (m, 1H), 3.66(m, 2H), 2.93 (t, 2H, J=7.5 Hz, 7.6 Hz), 2.21 (m, 2H), 1.74 (m, 2H),0.992 (t, 3H, J=7.1 Hz, 7.3 Hz). MS: m/z=476.2 (M+1)

EXAMPLE 48

Step 1: Preparation of 6-phenyldihydropyrimidine-2,4(1H,3H)-dione.

A neat mixture of (R)-(−)-2-phenylglycine (500 mg, 2.4795 mmol) andcarbamide (2 g, 33.3 mmol) was heated to 150° C. Et₃N (0.6913 mL, 4.959mmol) was added after the mixture melted. Stirring was continued at 150°C. for 4 hours followed by cooling to room temperature. The product wasdissolve in water at 100° C., then cool to room temperature. Productprecipitated out of the solution. The product was collected byfiltration and dried for use without purification.

Selected Signals: ¹H NMR (CD₃OH) δ 7.37 (m, 5H), 4.76 (m, 1H), 2.9 (m,1H), 2.75 (m, 1H).

Step 2: Preparation of6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione.

6-Phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared as in step 2 Example 47 above. The product was purified bypreparative TLC using ethyl acetate and hexane (70:30) to give the titlecompound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.57 (d, 1H J=8.7 Hz), 7.40 (m, 5H),7.05 (d, 1H, J=8.7 Hz), 5.65 (s, 1H)4.71 (m, 4H), 4.09(m, 4H), 3.0 (m,3H), 2.87 (m, 1H), 2.2 (m, 2H), 1.76 (m, 2H), 1.01 (t, 3H, J=7.6 Hz, 7.3Hz). MS: m/z=476.2 (M+1)

EXAMPLE 49

Preparation of5-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione.

5-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared as in step 2 Example 47 above from the chloride andcommercially available 5-methyl-dihydropyrimidine-2,4(1H,3H)-dione.

Selected Signals: ¹H NMR (CDCl₃) δ 7.56 (d, 1H J=8.7 Hz), 7.05 (d, 1H,J=8.9 Hz), 5.3 (s, 1H), 4.14 (t, 4H, J=6.2 Hz, 6.4 Hz), 4.02(m, 2H),3.72 (m, 1H), 2.96 (t, 2H, J=7.3 Hz, J=7.8 Hz), 2.76 (m, 1H), 2.47 (m,1H), 2.15 (m, 2H), 1.72 (m, 2H), 1.29 (d, 3H, J=6.2 Hz), 1.0 (t, 3H,J=7.6 Hz, 7.3 Hz).

EXAMPLE 50

To a mixture of5-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione(30 mg, 0.073 mmol), from Example 49, and NaOtBu (7.3 mg, 0.076 mmol) indry DMF (1 mL) was added MeI (6.8 μL, 0.109 mmol) at room temperature.Reaction mixture was stirred for 5 days. The reaction mixture waspartitioned between ethyl acetate and water. Combined organic extractswere washed with water and brine, dried over Na₂SO₄ and the solventevaporated in vacuo. The product was purified by preparative TLC usingethyl acetate and hexane (70:30) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.57 (d, 1H, J=8.7 Hz), 7.07 (d, 1H,J=8.9 Hz), 4.12 (m, 3H,), 4.0(m, 1H), 3.56 (m, 1H), 3.07 (s, 3H), 2.9(m, 3H,), 2.56 (m, 2H), 2.17 (m, 2H), 1.74 (m, 2H), 1.25 (d, 3H, J=6.6Hz), 1.0 (t, 3H, J=7.4 Hz, 7.3 Hz). MS: m/z=428.2 (M+1)

EXAMPLE 51

Step 1: Preparation of3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione.

A mixture 5,6-dihydrouracil (4.45 g, 39.028 mmol),3-{[tert-butyl(dimethyl)silyl]oxy}propan-1-ol (3 mL, 13.01 mmol) andCs₂CO₃ (16.95 g, 52.04 mmol) in dry DMF (120 mL) was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenethyl acetate and water. Combined organic extracts were washed withwater and brine, dried over Na₂SO₄ and the solvent evaporated in vacuo.Purified by chromatography on silica gel using ethyl acetate and hexane(60:40) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 5.48 (s, 1H), 3.86 (t, 2H, J=7.5 Hz,7.45 Hz), 3.68 (t, 2H, J=6.4 Hz, 6.4 Hz), 3.4 (m, 2H), 2.72 (t, 2H,J=6.7 Hz, 6.8 Hz), 1.81 (m, 2H), 0.91 (s, 9H), 0.06 (s, 6H).

Step 2: Preparation of3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1-phenyldihydropyrimidine-2,4(1H,3H)-dione.

A mixture of3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione(100 mg, 0.35 mmol), from this Example step 1, bromobenzene (0.037 mL,0.35 mmol), tris(dibenzylideneacetone)dipalladium (6.4 mg, 0.01 mmol),Xanthphos (0.0121 g, 0.021 mmol) and Cs₂CO₃ (0.171 g, 0.52 mmol) werecombined in dry dioxane (1 mL) and stirred at 100° C. overnight in asealed tube. The reaction mixture was partitioned between ethyl acetateand water. Combined organic extracts were washed with water and brine,dried over Na₂SO₄ and the solvent evaporated in vacuo. The product waspurified by preparative TLC using ethyl acetate and hexane (30:70) togive the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.43 (t, 2H, J=8.3 Hz, 7.5 Hz), 7.3(m, 3H), 3.94 (t, 2H), 3.82 (t, 2H, J=6.7 Hz, 6.8 Hz), 3.71 (t, 2H,J=6.4 Hz, 6.4 Hz), 2.88 (t, 2H, J=6.89 Hz, 6.6 Hz), 1.87 (m, 2H), 0.916(s, 9H), 0.074 (s, 6H).

Step 3: Preparation of3-(3-hydroxypropyl)-1-phenyldihdropyrimidine-2,4(1H,3H)-dione.

To a solution of3-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1-phenyldihydropyrimidine-2,4(1H,3H)-dione(115 mg, 0.318 mmol), from this Example step 2, in dry THF (3.5 mL) wasadded tetra-butylammonium fluoride (1.0 M THF, 0.477 ml, 0.476 mmol) at0° C. The reaction was stirred from 0° C. to room temperature for 2hours. Saturated NaHCO₃ was added, and the mixture extracted with CH₂Cl₂three times. Extracts were dried over Na₂SO₄ and the solvent evaporatedin vacuo. The product was purified by preparative TLC using ethylacetate and hexane (80:20) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.44 (t, 2H, J=8.5 Hz, 7.4 Hz),7.3(m, 3H), 4.02 (t, 2H, J=6.2 Hz, 5.9 Hz), 3.85 (t, 2H, J=6.9 Hz, 6.6Hz), 3.60 (m, 2H), 3.072 (t, 1H, J=6.8 Hz, 6.9 Hz) 2.92 (m, 2H), 1.867(m, 2H).

Step 4: Preparation of1–1,2-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxypropyl)dihydropyrimidine-2,4(1H,3H)-dione.

To a mixture of 6-hydroxy-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole(56.7 mg, 0.23 mmol),3-(3-hydroxypropyl)-1-phenyldihydropyrimidine-2,4(1H,3,H)-dione (0.0574g, 0.231 mmol), from this Example step 3, and triphenylphosphine (78.9mg, 0.30 mmol) in dry benzene (1.3 mL) was addeddiisopropylazodicarboxylate (0.059 mL, 0.30 mmol). The reaction mixturewas stirred at room temperature overnight. The solvent was evaporated invacuo and the product purified by preparative TLC using 40% diethylether/hexane then 70% diethyl ether/hexane to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 7.56 (d, 1H, J=8.9 Hz), 7.31 (m, 5H),7.08 (d, 1H, J=9 Hz), 4.19 (t, 2H, J=6.4 Hz, 6.4 Hz), 4.103 (t, 2H,J=7.2 Hz, 7.3 Hz), 3.85 (t, 2H, J=6.7 Hz, 6.8 Hz), 2.96 (t, 2H, J=7.4Hz, 7.7 Hz), 2.92 (t, 2H, 6.6 Hz, 6.6 Hz), 2.25 (m, 2H), 1.74 (m, 2H),0.993 (t, 3H, J=7.3 Hz, 7.4 Hz). MS: m/z=476.0 (M+1)

EXAMPLE 52

Step 1: Preparation of3-(3-hydroxypropyl)-1-pyridin-2-yldihydroprimidine-2,4(1H,3H)-dione.

3-(3-Hydroxypropyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione wasprepared as for Example 51 step 2 and 3 starting from 2-bromopyridine.

Selected Signals: ¹H NMR (CDCl₃) δ 8.4 (m, 1H), 7.8(d, 1H), 7.76 (m,1H), 7.15 (m, 1H), 4.2 (t, 2H, 7.4 Hz, 6.2 Hz), 4.05 (t, 2H, J=6.2 Hz,6.2 Hz), 3.61 (t, 1H), 3.5 (m, 1H, J=7.0 Hz), 2.9 (t, 2H, J=6.7 Hz, 6.6Hz), 1.89(m, 2H).

Step 2: Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione.

3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dionewas prepared as for Example 51 step 4. The product was purified bypreparative TLC using ethyl acetate and hexane (50:50) to give the titlecompound.

Selected Signals: ¹H NMR (CDCl₃) δ 8.4 (m, 1H), 7.81(d, 1H, J=8.5 Hz),7.4 (m, 1H), 7.57 (d, 1H, J=8.7 Hz), 7.13 (m, 1H) 7.07 (d, 1H J=8.7),4.16 (m, 6H), 2.96 (t, 2H, J=7.4 Hz, 7.5 Hz), 2.88 (t, 2H, J=6.6 Hz, 6.7Hz), 2.23 (m, 2H,), 0.995 (t, 3H, J=7.6 Hz, 7.2 Hz). MS: m/z=477.2 (M+1)

EXAMPLE 53

Step 1. Preparation of3-(3-hydroxypropyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione.

3-(3-Hydroxypropyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione wasprepared as for Example 51 step 2 and 3 starting from 2-bromopyrimidine.The product was purified by preparative TLC using ethyl acetate andhexane (80:20) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 8.73 (d, 2H, J=4.8 Hz), 7.14 (t, 1H,J=4.8 Hz), 4.1 (t, 1H, J=6.4 Hz, 6.6 Hz), 3.97 (t, 2H), 3.71 (t, 2H,J=6.4 Hz, 6.2 Hz), 2.87 (t, 2H, J=6.4 Hz, 6.7 Hz), 1.89 (m, 2H), 0.903(s, 9H), 0.061 (s, 6H).

Step 2: Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione.

3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dionewas prepared as for Example 51 step 4. The product was purified bypreparative TLC using ethyl acetate and hexane (70:30) then 100% ethylacetate to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 8.75 (d, 1H, J=4.8 Hz), 7.56(d, 1H,J=8.9 Hz), 7.17 (t, 1H, J=4.8 Hz, 4.8 Hz), 7.07 (d, 1H, J=8.9 Hz), 4.15(m, 6H), 2.93 (m, 4H), 2.27 (m, 2H), 1.74 (m, 2H,), 0.988 (t, 3H, J=7.3Hz, 7.6 Hz). MS: m/z=478.2 (M+1)

EXAMPLE 54

Step 1: Preparation of3-(3-hydroxypropyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dione.

3-(3-Hydroxypropyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dione wasprepared as for Example 51 step 2 and 3 starting from 5-bromopyrimidine.

The product was purified by preparative TLC using ethyl acetate andhexane (80:20) to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 9.11 (s, 1H), 8.797(s, 2H), 4.04 (t,2H, J=6.1 Hz, 6.4 Hz), 3.93 (t, 2H, J=6.6 Hz, 6.9 Hz), 3.63 (t, 2H,J=5.7 Hz, 5.5 Hz), 3.0 (t, 2H, J=6.6 Hz, 6.7 Hz), 1.88 (m, 2H).

Step 2: Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dione.

3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dionewas prepared as for Example 51 step 4. The product was purified bypreparative TLC using ethyl acetate and hexane (70:30) then 100% ethylacetate to give the title compound.

Selected Signals: ¹H NMR (CDCl₃) δ 9.11 (s, 1H), 8.799(s, 2H), 7.57 (d,1H, J=8.7 Hz), 7.07 (d, 1H, J=8.7 Hz), 4.19 (t, 2H, J=6.2 Hz, 6.2 Hz),4.13 (t, 2H, J=7.1 Hz, 7.3 Hz), 3.93 (t, 2H, J=6.8 Hz, 6.7 Hz), 2.98 (m,4H), 2.1 (m, 2H), 1.74 (m, 2H), 0.995 (t, 3H, J=7.3 Hz, 7.5 Hz). MS:m/z=478.2 (M+1)

EXAMPLE 55

Preparation of1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}-propyl)piperidin-2-one.

1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-onewas prepared as for Example 10 from piperidin-2-one and the bromide fromExample 9. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.3 (d 2H, J=8.6 Hz), 6.90(d, 2H, J=8.6 Hz), 3.63 (t, 2H, J=7.2 Hz), 3.29 (m, 2H), 2.82 (s, 2H),2.14 (m, 2H), 1.85 (m, 4H), 1.71 (sext, 2H, J=7.4 Hz), 0.986 (t, 3H,J=7.3 Hz).

EXAMPLE 56

Preparation of1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one.

1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-onewas prepared as for Example 10 from piperidin-2-one and the bromide fromExample 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.57 (d, 1H, J=8.8 Hz); 7.06(d, 1H, J=8.8 Hz); 4.15 (t, 2H, J=6.2 Hz); 3.63 (t, 2H, J=7.4 Hz); 3.40(t, 2H, J=5.6 Hz); 2.93 (t, 2H, J=6.2 Hz); 2.51 (t, 2H, J=6.2); 2.16(pentet, 2H, J=6.7 Hz); 1.90–1.8 (m, 4H); 1.73 (sextet, 2H, J=7.5 Hz);0.99 (t, 3, J=7.6 Hz).

EXAMPLE 57

Preparation of1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione.

1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-piperidin-2,6-dionewas prepared as for Example 10 from piperidin-2,6-dione and the bromidefrom Example 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; C₆D₆) δ 6.43 (d, 1H, J=8.8 Hz); 3.90(t, 2H, J=7.4 Hz); 3.51 (t, 2H, J=6.4 Hz); 2.93 (t, 2H, J=7.6 Hz);1.91–1.82 (m, 6H); 1.72 (sextet, 2H, J=7.5 Hz); 0.95 (t, 3H, J=7.4 Hz);0.83 (pentet, 2H, J=6.6 Hz).

EXAMPLE 58

Preparation of1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione.

1-(3-{[7-Propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dionewas prepared as for Example 10 from piperidin-2,5-dione and the bromidefrom Example 27. After aqueous work-up and silica gel chromatography,the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.96–7.93 (m, 2H); 7.66 (d,1H, J=8.8 Hz); 7.58–7.53 (m, 3); 6.98 (d, 1H, J=8.4 Hz); 4.12 (t, 2H,J=6.2 Hz); 4.04 (t, 2H, J=7.2 Hz); 2.97 (t, 2H, J=7.6 Hz); 2.69 (t, 4H,J=6.4 Hz); 2.10 (pentet, 2H, J=6.7 Hz); 1.96 (pentet, 2H, J=6.6 Hz);1.77 (sextet, 2H, J=7.6 Hz); 1.02 (t, 3H, J=7.4 Hz).

EXAMPLE 59

Preparation of4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dione.

4-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dionewas prepared as for Example 10 from morpholine-3,5-dione and the bromidefrom Example 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.57 (d, 1H, J=8.8 Hz); 7.04(d, 1H, J=8.8 Hz); 4.38 (s, 4H); 4.14 (t, 2H, J=6.0 Hz); 4.07 (t, 2H,J=7.2 Hz); 2.96 (t, 2H, J=7.4 Hz); 2.16 (pentet, 2H, J=6.6 Hz); 1.74(sextet, 2H, J=7.5 Hz); 1.00 (t, 3H, J=7.2 Hz).

EXAMPLE 60

Preparation of1-(3-}[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2,5-dione.

1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2,5-dionewas prepared as for Example 10 from piperazine-2,5-dione and the bromidefrom Example 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.58 (d, 1H, J=8.8 Hz); 7.06(d, 1H, J=8.8 Hz); 6.41 (s, 1H); 4.17 (t, 2H, J=6.0 Hz); 4.09 (s, 2H);3.68 (t, 2H, J=7.2 Hz); 2.94 (t, 2H, J=7.6 Hz); 2.18 (pentet, 2H, J=7.0Hz); 1.74 (sextet, 2H, J=7.5 Hz); 1.00 (t, 3H, J=7.4).

EXAMPLE 61

Preparation of4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-one.

4-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-onewas prepared as for Example 10 from piperazine-2-one and the bromidefrom Example 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CD₃OD) δ 7.64 (d, 1H, J=8.8 Hz); 7.27(d, 1H, J=8.8 Hz); 4.21 (t, 2H, J=6.0 Hz); 3.85 (s, 1H); 3.71 (t, 2H,J=7.2 Hz); 3.68 (t, 2H, J=5.4 Hz); 2.96 (t, 2H, J=7.6 Hz); 2.16 (pentet,2H, J=7.0 Hz); 1.73 (sextet, 2H, J=7.5 Hz); 0.98 (t, 3H, J=7.4 Hz).

EXAMPLE 62

Preparation of3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3,5-triazinane-2,4-dione.

3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3,5-triazinane-2,4-dionewas prepared as for Example 10 from triazinane-2,4-dione and the bromidefrom Example 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.56 (d, 1H, J=8.8 Hz); 7.06(d, 1H, J=8.8 Hz); 5.7 (s, 2H) 4.54 (t, 2H, J=2.4 Hz); 4.17 (t, 2H,J=6.2 Hz); 3.98 (t, 2H, J=7.0 Hz); 2.96 (t, 2H, J=7.4 Hz); 2.22 (pentet,2H, J=6.8 Hz); 1.73 (sextet, 2H, J=7.4 Hz); 0.99 (t, 3H, J=7.4 Hz).

EXAMPLE 63

Preparation of3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione.

3-(3-{[7-Propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared as for Example 10 from dihydropyrimidine-2,4(1H,3H)-dioneand the bromide from Example 27. After aqueous work-up and silica gelchromatography, the title compound was obtained.

Selected Signals: ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.94 (m, 2H); 7.66 (d,1H, J=8.8 Hz); 7.58–7.53 (m, 3H); 6.99 (d, 1H J=8.8 Hz); 5.87 (s, 1H);4.14 (t, 2H, J=6.2 Hz); 4.04 (t, 2H, J=7.2 Hz); 3.40 (td, 2H, J₁=7.0 Hz,J₂=2.5 Hz); 2.98 (t, 2H, J=7.6 Hz); 2.74 (t, 2H, J=6.8 Hz); 2.16(pentet, 2H, J=7.0 Hz); 1.77 (sextet, H, J=7.6 Hz); 1.02 (t, 3H, J=7.4Hz).

EXAMPLE 64

Preparation of6-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyimidine-2,4(1H,3H)-dione.

6-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared as for Example 10 from6-methyldihydropyrimidine-2,4(1H,3H)-dione and the bromide from Example7. After aqueous work-up and silica gel chromatography, the titlecompound was obtained.

Selected Signals: ¹H NMR (400 MHz; CDCl₃) δ 7.55 (d, 1H, J=8.8 Hz), 7.05(d, 1H, J=8.8 Hz), 4.14 (t, 2H, J=6.2 Hz), 4.02 (clean nine linepattern, 2H, J=7.1 Hz), 3.72 (m, 1H), 2.96 (collapsed dd, 2H, J=7.5 Hz),2.76 (ddd, B of ABX, 1H, J=16.4, 4.0, 1.6 Hz), 2.47 (dd, A of ABX, 1H,J=16.4, 10.4 Hz), 2.16 (pent, 2H, J=6.8 Hz), 1.73 (sext, 2H, J=7.6 Hz),1.29 (d, 3H, J=6.4 Hz), 0.994 (t, 3H, J=7.4 Hz).

EXAMPLE 65

Preparation of1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one.

1-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-onewas prepared as for Example 10 from caprolactam and the bromide fromExample 7. After aqueous work-up and silica gel chromatography, thetitle compound was obtained.

Characteristic NMR Resonances; ¹H NMR 400 MHz (CDCl₃); δ 7.57 (d, 1H,J=8.8 Hz); 7.07 (d, 1H, J=8.8 Hz); 4.13 (t, 2H, J=6.4 Hz); 3.63 (t, 2H,J=7.2 Hz); 3.45–3.43 (m, 2H); 2.93 (t, 2H, J=7.6 Hz); 2.60–2.57 (m, 2H);2.12 (pentet, 2H, J=7.0 Hz); 1.77–1.67 (m, 8H); 0.99 (t, 3H, J=7.4 Hz).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the particulardosages as set forth herein above may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for any ofthe indications for the active agents used in the instant invention asindicated above. Likewise, the specific pharmacological responsesobserved may vary according to and depending upon the particular activecompound selected or whether there are present pharmaceutical carriers,as well as the type of formulation employed, and such expectedvariations or differences in the results are contemplated in accordancewith the objects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of formula I

or a pharmaceutically acceptable salt, ester or tautomer thereof,wherein R¹ is selected from the group consisting of: (a) —CF₃, (b)—CH₂C(CH₃)₃, (c) phenyl, unsubstituted, mono- or poly-substituted withhalo, (d) —C₁₋₆ alkyl, and (e) —C₁₋₂alkyl-phenyl; R² is selected fromthe group consisting of: (a) —C₁₋₆ alkyl, (b) —COOR³, (c) —CR³R⁴—O—R⁵,(d) —CR³R⁴—S—R⁵, and (e) —COR³; R³, R⁴ and R⁵ are independently selectedat each occurrence from the group consisting of —H, phenyl, and C₁₋₆alkyl; Y is joined together with the nitrogen and the carbonyl carbonshown in Formula I to which Y is respectively attached, to form aheterocyclic ring selected from: (a) a 5-membered heterocyclic ringselected from the group consisting of:

(b) a 6-membered heterocyclic ring selected from the group consistingof:

provided that when R₁ is —CF₃, R₂ is n-propyl, and Z is n-propyloxy, the6-membered heterocyclic ring is not unsubstituted 5,6 dihydrouracil,

(d) a bicyclic heterocyclic ring selected from the group consisting of:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷; R⁶ isindependently selected at each occurrence from the group consisting of:(a) —H, (b) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —OH, —NR³R⁴,—OR³, —COOR³, and —CN, (c) —C₁₋₆alkyl-phenyl, unsubstituted, mono- orpoly-substituted with a substituent selected from the group consistingof halo, —C₁₋₃alkyl, and —COOR³, (d) —C₃₋₆cycloalkyl, unsubstituted,mono- or poly-substituted with a substituent selected from the groupconsisting of halo, —OH, —OR³, —COOR³, and —CN, (e)—C₃₋₆cycloheteroalkyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —OH,—(CH₂)_(n)OR³, —OR³, —COOR³, and —CN, wherein n is an integer selectedfrom 2, 3, 4, 5 and 6, (f) —C₂₋₆alkenyl, (g) —C(O)C₁₋₆alkyl, (h) —COOR³,(i) —C(O)—(CH₂)_(p)—COOR³, wherein p is an integer selected from 2, 3and 4, (j) phenyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, (k) pyridyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, (l) pyrimidinyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, (m) pyrazinyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, and (n) thiazolyl, unsubstituted, mono- or poly-substituted witha substituent selected from the group consisting of halo, —C₁₋₃alkyl,and —COOR³; R⁷ is independently selected at each occurrence from thegroup consisting of: (a) ═O, (b) —C₁₋₆alkyl-phenyl, unsubstituted, mono-or poly-substituted with a substituent selected from the groupconsisting of halo, —CN, —COOR³, —COR³, and —OH, (c) —C₁₋₆alkyl,unsubstituted, mono- or poly-substituted with a substituent selectedfrom the group consisting of halo, —OH, —COOR³, tetrazole and —CN, (d)—C₃₋₆ cycloalkyl, (e) —C₃₋₆ spiroalkyl, (f) —COOR³, (g) halo, (h)—NR³R⁴, (i) phenyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —COOR³ and—C₁₋₄alkyl, (j) pyridyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, (k) pyrimidinyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, and (l) pyrazinyl, unsubstituted, mono- or poly-substituted witha substituent selected from the group consisting of halo, —C₁₋₃alkyl,and —COOR³; and Z is selected from the group consisting of: (a)—C₁₋₆alkyl-, (b) —C₁₋₆alkyl-O—, (c) —C₃₋₆cycloalkyl-, and (d)—C₃₋₆cycloalkyl-O—; and wherein the pharmaceutically acceptable ester ofthe compound of formula I is selected from the group consisting of (a) aphenyl ester, (b) a —C₁₋₆alkyl ester and (c) a substituted C₁₋₄alkylester wherein the substituent is selected from the group consisting ofphenyl-, dimethylamino- and acetylamino-.
 2. The compound of claim 1wherein Z is —C₂₋₄alkyl-O—.
 3. The compound of claim 2 wherein R¹ isselected from the group consisting of: (a) —CF₃, (b) —CH₂C(CH₃)₃, and(c) phenyl, unsubstituted, mono- or poly-substituted with halo; and R²is selected from the group consisting of: (a) —C₁₋₆ alkyl, and (b)—COR³.
 4. The compound of claim 3 wherein R² is n-propyl.
 5. Thecompound of claim 4 wherein Y is joined together with the nitrogen andthe carbonyl carbon shown in Formula I to which Y is respectivelyattached, to form a heterocyclic ring selected from: (a) a 5-memberedheterocyclic ring selected from the group consisting of:

(b) a 6-membered heterocyclic ring selected from the group consistingof:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.
 6. Thecompound of claim 5 wherein R⁶ is independently selected at eachoccurrence from the group consisting of: (a) —H, (b) —C₁₋₆alkyl,unsubstituted, mono- or poly-substituted with a substituent selectedfrom the group consisting of halo, —OH, —NR³R⁴, —OR³, —COOR³, and —CN,(c) —C₁₋₆alkyl-phenyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, (d) —C(O)—(CH₂)_(p)—COOR³, wherein p is an integer selected from2, 3 and 4, (e) phenyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, (f) pyridyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —C₁₋₃alkyl, and—COOR³, and (g) pyrimidinyl, unsubstituted, mono- or poly-substitutedwith a substituent selected from the group consisting of halo,—C₁₋₃alkyl, and —COOR³.
 7. The compound of claim 6 wherein R⁷ isindependently selected from the group consisting of: (a) ═O, (b)—CH₂-phenyl, unsubstituted, mono- or poly-substituted with a substituentselected from the group consisting of halo, —CN, —COOR³, —COR³, and —OH,(c) —C₁₋₆alkyl, unsubstituted, mono- or poly-substituted with asubstituent selected from the group consisting of halo, —OH, —COOR³,tetrazole and —CN, (d) halo, (e) —NH₂, (f) phenyl, unsubstituted, mono-or poly-substituted with a substituent selected from the groupconsisting of halo, —COOR³ and —C₁₋₄alkyl, and (g) pyridyl,unsubstituted, mono- or poly-substituted with a substituent selectedfrom the group consisting of halo, —C₁₋₃alkyl, and —COOR³.
 8. Thecompound of claim 2 wherein R¹ is selected from the group consisting of:(a) —CF₃, and (b) phenyl, unsubstituted, mono- or poly-substituted withhalo.
 9. The compound of claim 8 wherein Y is joined together with thenitrogen and the carbonyl carbon shown in Formula I to which Y isrespectively attached, to form a heterocyclic ring selected from: (a) a5-membered heterocyclic ring selected from the group consisting of:

(b) a 6-membered heterocyclic ring selected from the group consistingof:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.
 10. Thecompound of claim 2 wherein R¹ is —CF₃.
 11. The compound of claim 10wherein Y is joined together with the nitrogen and the carbonyl carbonshown in Formula I to which Y is respectively attached, to form aheterocyclic ring selected from: (a) a 5-membered heterocyclic ringselected from the group consisting of:

(b) a 6-membered heterocyclic ring selected from the group consistingof:

wherein each carbon atom in the heterocyclic ring, formed when Y isjoined together with the nitrogen and the carbonyl carbon shown inFormula I, is independently unsubstituted, mono- or di-substituted witha substituent independently selected at each occurrence from R⁷.
 12. Thecompound of claim 1 wherein Z is —C₃₋₆cycloalkyl-O—.
 13. The compound ofclaim 1 wherein Z is —C₄₋₆alkyl-.
 14. A compound selected from the groupconsisting of: (1)1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;(2)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;(3)2-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1H-isoindole-1,3(2H)-dione;(4)3,3-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;(5)3-methyl-3-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;(6)3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;(7)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;(8)5,5-dimethyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;(9)[2,4-dioxo-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3-thiazolidin-5-yl]aceticacid; (10)3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(11)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(12)1-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(13)5(R)-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(14)5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(15)1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(16)5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(17)5-methyl-5-phenyl-3-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(18)5-methyl-5-phenyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(19)5-methyl-5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione;(20)5-methyl-5-(3-carboxyphenyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(21)5-methyl-5-(4-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(22)5-methyl-5-(3-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(23)5-methyl-5-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(24)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrimidin-2-ylimidazolidine-2,4-dione;(25)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyrazin-2-ylimidazolidine-2,4-dione;(26)3-[2,5-dioxo-4-phenyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-4-yl]propanoicacid; (27)4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]butanoicacid; (28)4-[5,5-dimethyl-2,4-dioxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]pentanoicacid; (29)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one;(30) methyl2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoate;(31)2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoicacid; (32)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(33)5,5-dimethyl-1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(34)1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione;(35)1-[trans-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclopentyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione;(36)1-{4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butyl}dihydropyrimidine-2,4(1H,3H)-dione;(37)5-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(38)6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(39)5-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(40)1,5-Dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(41)1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(42)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione;(43)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H1,2′-bipyrimidine-2,4(3H)-dione;(44)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,5′-bipyrimidine-2,4(3H)-dione;(45)1-(3-{[7-propyl-3-(neopentyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one;(46)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one;(47)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione;(48)1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione;(49)4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)morpholine-3,5-dione;(50)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2,5-dione;(51)4-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperazine-2-one;(52)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1,3,5-triazinane-2,4-dione;(53)3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(54)6-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;and (55)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one;and pharmaceutically acceptable salts, esters and tautomers thereof,wherein the pharmaceutically acceptable ester are selected from thegroup consisting of (a) a phenyl ester, (b) a —C₁₋₆alkyl ester and (c) asubstituted —C₁₋₄alkyl ester wherein the substituent is selected fromthe group consisting of phenyl-, dimethylamino- and acetylamino-.
 15. Amethod for treating dyslipidemia comprising administering atherapeutically effective amount of a compound of claim 1 to a patientin need thereof.
 16. The method of claim 15 wherein the dyslipidemiacomprises depressed plasma HDL cholesterol level.
 17. A method fortreating atherosclerosis comprising administering a therapeuticallyeffective amount of a compound of claim 1 to a patient in need thereof.18. A pharmaceutical composition comprised of a compound of claim 1 anda pharmaceutically acceptable carrier.
 19. A compound selected from thegroup consisting of: (1)11-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-2-one;(2)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)pyrrolidine-2,5-dione;(3)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)thiazolidine-2,4-dione;(4)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(5)1-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(6)5,5-dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(7)1-Phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(8)1-(2-pyridyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(9)5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(10)5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}butyl)imidazolidine-2,4-dione;(11)5-Phenyl-5-methyl-3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(12)5-(3-carboxyphenyl)-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(13)5-(2-Pyridyl)-5-methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(14)5-Phenyl-5-(3-propionyl)-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione;(15)2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoicacid; (16)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2-one;(17)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,6-dione;(18)1-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)piperidin-2,5-dione;(19)1-[cis-2-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}cyclohexyl)methyl]dihydropyrimidine-2,4(1H,3H)-dione;(20)3-(3-{[7-propyl-3-(phenyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-dihydropyrimidine-2,4(1H,3H)-dione;(21)6-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(22)1-phenyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)dihydropyrimidine-2,4(1H,3H)-dione;(23)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-1-pyridin-2-yldihydropyrimidine-2,4(1H,3H)-dione;(24)3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)-5,6-dihydro-2H-1,2′-bipyrimidine-2,4(3H)-dione;and (25)1-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)azepan-2-one,and pharmaceutically acceptable salts, esters and tautomers thereof,wherein the pharmaceutically acceptable ester are selected from thegroup consisting of (a) a phenyl ester, (b) a —C₁₋₆alkyl ester and (c) asubstituted —C₁₋₄alkyl ester wherein the substituent is selected fromthe group consisting of phenyl-, dimethylamino- and acetylamino-.